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Fatty Liver Disease (MASLD/NAFLD)

What Is It?

• NAFLD (Nonalcoholic Fatty Liver Disease) - older term, still widely used
• MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) - the current preferred term adopted in 2023, emphasizing the metabolic driver
• MASH (Metabolic Dysfunction-Associated Steatohepatitis) - replaces NASH

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Spectrum of Disease

• Progression is non-linear - some patients cycle between NAFL and NASH
• ~20% of NASH patients are rapid progressors to advanced fibrosis
• Fibrosis regression is possible with treatment

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Risk Factors / Associated Conditions

• Obesity (especially central/visceral adiposity)
• Type 2 diabetes mellitus or insulin resistance
• Dyslipidemia (hypertriglyceridemia, low HDL, high LDL)
• Hypertension
• Metabolic syndrome (all of the above)

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Pathogenesis

1. Insulin resistance - the central driver. It increases adipose tissue lipolysis, flooding the liver with free fatty acids (FFAs). Reduced adiponectin further impairs FFA oxidation in skeletal muscle and increases hepatocyte FFA uptake.
2. Hepatic lipotoxicity - accumulated lipids (especially saturated FFAs like palmitate and lysophosphatidylcholine) directly injure hepatocytes via:
   • Endoplasmic reticulum (ER) stress
   • Mitochondrial dysfunction
   • Lysosomal dysfunction
   • Reactive oxygen species (ROS) production
   • Inflammasome activation → IL-1 release
3. Hepatocyte ballooning - ballooned hepatocytes produce sonic hedgehog, which activates hepatic stellate cells (HSCs) in a paracrine fashion → collagen deposition → fibrosis
4. Innate immune activation - gut-derived endotoxins (via dysbiosis and increased gut permeability) activate Kupffer cells and inflammatory signaling
5. Genetic factors - the PNPLA3 rs738409 variant (C>G polymorphism) is the strongest genetic risk factor for both disease severity and HCC risk
6. Gut microbiome dysbiosis - independently contributes to inflammation and bile acid signaling changes

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Clinical Features

• Most patients are asymptomatic - often an incidental finding
• Symptoms, when present: fatigue, malaise, right upper quadrant discomfort
• Labs: elevated ALT and AST, with AST:ALT ratio typically <1 (key differentiator from alcoholic liver disease, where AST:ALT >2)
• Hepatomegaly may be present on examination
• Advanced disease shows signs of chronic liver disease/cirrhosis

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Diagnosis

• Ultrasound - most common screening tool; detects steatosis >20-33% of hepatocytes
• FIB-4 score (using age, AST, ALT, platelets) - initial fibrosis risk stratification
• Transient elastography (FibroScan) with CAP (controlled attenuation parameter)
• MRI-PDFF (proton density fat fraction) - most accurate quantification of steatosis
• MR elastography - most accurate non-invasive fibrosis assessment

• Diagnosing NASH/MASH (distinguishing from simple steatosis)
• Staging fibrosis accurately
• Graded by the NAFLD Activity Score (NAS): steatosis (0-3) + lobular inflammation (0-3) + ballooning (0-2); NAS ≥5 = NASH

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Complications / Outcomes

1. Cardiovascular disease (most common overall cause of death)
2. Cirrhosis
3. Non-liver malignancy
4. Hepatocellular carcinoma (HCC)
5. Diabetes mellitus

• In NASH specifically, liver-related mortality surpasses cardiovascular mortality
• NAFLD-related HCC is growing 9% annually in the US
• NAFLD is a major contributor to "cryptogenic" cirrhosis
• Shares risk factors with coronary artery disease

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Treatment

Lifestyle (cornerstone)

• ≥5% body weight loss - improves steatosis, ballooning, and inflammation
• ≥7-10% weight loss - improves fibrosis; 10%+ achieves greatest fibrosis resolution
• Mediterranean-style diet (reduced refined carbs, saturated fat)
• Aerobic exercise (even without weight loss, reduces hepatic fat)
• Avoid sugar-sweetened beverages and fructose

Bariatric/Metabolic Surgery

• Proven to improve NASH histology and induce fibrosis regression
• Considered in obese patients with BMI ≥35 with metabolic comorbidities

Pharmacological

• Resmetirom (Rezdiffra) - thyroid hormone receptor-beta (THR-β) agonist; first-ever FDA-approved drug specifically for MASH with fibrosis (approved March 2024)
• Semaglutide (Ozempic/Wegovy) - GLP-1 receptor agonist; AASLD updated guidance in November 2025 supports use for MASH; meta-analysis confirms efficacy (PMID 40489581)

• SGLT2 inhibitors (empagliflozin, dapagliflozin)
• Pioglitazone (in patients with T2DM, improves steatohepatitis)
• Vitamin E (in non-diabetic adults with NASH)
• FGF19/FGF21 analogs, PPAR agonists (phase 3 trials)

Cardiovascular Risk Management

• Statins are safe in NAFLD and should be used for dyslipidemia management
• Control of hypertension, diabetes, and hyperlipidemia is integral to care

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Pediatric NAFLD

• Growing problem paralleling pediatric obesity epidemic
• Distinct histology: inflammation and scarring are more prominent in portal tracts/periportal regions (vs. centrilobular in adults), with mononuclear (not neutrophilic) infiltrates predominating

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Key Differentials

• Alcoholic fatty liver - AST:ALT >2, history of alcohol use, GGT often elevated
• Drug-induced steatosis - amiodarone, methotrexate, tamoxifen, valproate, corticosteroids
• Acute fatty liver of pregnancy (AFLP) - obstetric emergency
• Lipodystrophy, hypothyroidism, celiac disease

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• Robbins & Kumar Basic Pathology, 10th ed.
• Yamada's Textbook of Gastroenterology, 7th ed.
• AASLD Practice Guidance on MASLD (updated 2023-2025), aasld.org
• GLP-1 therapies for MASH meta-analysis (Wang et al., 2025) - PMID 40489581
• Global epidemiology in T2DM meta-analysis (Younossi et al., 2024) - PMID 38521116

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Cervical Radiculopathy

Definition

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Etiology and Pathophysiology

1. Disc Herniation (younger patients, <45 years)

• Nucleus pulposus extrudes through the annulus fibrosus and compresses the adjacent nerve root
• More likely to present acutely
• Biochemical irritation from inflammatory mediators (phospholipase A2, cytokines) also contributes - not purely mechanical compression

2. Foraminal Stenosis from Degenerative Changes (older patients, >45 years)

• Uncovertebral joint osteophytes (posterolateral) and facet joint osteophytes narrow the intervertebral foramen
• Cervical spondylosis - degenerative disc disease with disc height loss, osteophyte formation, ligamentum flavum hypertrophy
• Becomes more prevalent with increasing age; the more common cause overall

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Nerve Root Level Localization

• C8/T1 clinically evident compression is less common
• Subscapular/interscapular pain is characteristic of lower cervical roots (C7 especially, also C6, C8, T1)
• Radicular pain is worsened by Valsalva/coughing (increased intradiscal pressure)

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Clinical Presentation

• Neck pain radiating down the arm in a dermatomal pattern
• Paresthesias, dysesthesias, numbness in the corresponding dermatome
• Weakness of muscles innervated by the affected root (myotome)
• Reflex diminution or loss (lower motor neuron at the level of the lesion)

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Physical Examination

Key Provocative Tests

• Neck extension + lateral rotation toward the symptomatic side + downward axial compression
• Reproduces or worsens radicular arm pain
• A 2025 systematic review and meta-analysis (PMID 39938056) confirms good specificity for subacute/chronic cervical radiculopathy; best used to confirm, not exclude

• Placing the hand on top of the head relieves radicular pain (reduces nerve root tension)
• Highly specific for cervical radiculopathy

• Manual axial traction of the head by the examiner relieves arm pain
• Positive when it reduces radicular symptoms

• Neurodynamic test analogous to the straight-leg raise for lumbar radiculopathy
• A 2025 meta-analysis (PMID 40156954) evaluated diagnostic accuracy of neurodynamic tests for upper-limb entrapment/radicular pathology

Warning Signs of Myelopathy (not radiculopathy alone)

• Spread of biceps reflex to finger flexors (inverted biceps reflex)
• Paradoxical biceps reflex (absent biceps + reflex contraction of finger flexors/triceps)
• Increased triceps reflex with absent biceps reflex
• Hoffman's sign, clonus, Babinski sign
• Gait disturbance, leg spasticity

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Diagnostic Testing

Imaging

• Identifies nerve root compression, disc herniation, foraminal stenosis, and spinal cord changes
• Must be interpreted cautiously - degenerative abnormalities are extremely common in the asymptomatic spine
• Indicated when: symptoms persist >4-6 weeks without improvement, progressive neurologic deficit, red flags present, or surgery/injection being considered

• More sensitive than MRI in some cases
• Better at distinguishing osteophyte/calcified disc from soft disc herniation
• Preferred when: MRI contraindicated (pacemaker, spinal cord stimulator), prior hardware from cervical fusion (causes MRI artifact), severe claustrophobia
• Limitation: Cannot visualize lateral disc herniation beyond the subarachnoid space

Electrodiagnostic Studies (EMG/NCS)

• Reduced CMAP amplitude (motor) - affected
• Preserved SNAP amplitude (sensory) - preserved despite sensory symptoms

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Differential Diagnosis

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Treatment

Natural History

Conservative (Non-operative) Management - First Line

• NSAIDs - analgesic and anti-inflammatory; first-choice oral agent
• Short-course oral corticosteroids - may provide faster initial pain relief
• Neuropathic agents - gabapentin, pregabalin for neuropathic/radicular pain component
• Muscle relaxants - for associated cervical muscle spasm (short-term)
• Opioids - generally avoided unless severe, refractory, short-term

• Cervical traction (mechanical or manual) - decompresses neural foramen
• Therapeutic exercise, postural training
• Manual therapy / mobilization - supported by a 2025 umbrella review (PMID 39607420) for neck disorders
• Soft cervical collar - temporary/situational use only; prolonged use leads to deconditioning

• Can provide significant short-term pain relief and facilitate rehabilitation
• Interlaminar or transforaminal approach
• Best evidence for acute-to-subacute radiculopathy with significant pain
• Bridging therapy while awaiting natural resolution or surgery

Surgical Management

1. Absolute: Rapidly progressive or severe motor weakness, myelopathy
2. Relative: Intractable pain not responding to ≥6-12 weeks of conservative care; significant neurologic deficit persisting

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Red Flags - Urgent Assessment Required

• Myelopathy signs: Gait instability, bilateral arm/leg symptoms, hyperreflexia, bladder/bowel dysfunction
• Trauma history with neurologic deficit
• Cancer history (metastatic cord compression)
• Fever + neck pain (epidural abscess, discitis)
• Progressive rapid weakness (surgical emergency)

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• Bradley and Daroff's Neurology in Clinical Practice, 8th ed.
• Firestein & Kelley's Textbook of Rheumatology
• Spurling's test diagnostic accuracy meta-analysis (Lin et al., 2025) - PMID 39938056
• Manual therapy for neck disorders umbrella review (Reynolds et al., 2025) - PMID 39607420
• Neurodynamic tests meta-analysis (Albert-Lucena et al., 2025) - PMID 40156954
• ACR Appropriateness Criteria: Cervical Pain/Radiculopathy 2024

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NAFLD/MASLD: Staging, Diagnostic Criteria, Clinical Thinking, History & Examination

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1. The Diagnostic Framework - How to Think About It

1. Confirm the presence of steatosis (imaging or biopsy)
2. Exclude other causes of liver disease (alcohol, drugs, other)
3. Stage the disease - is it simple steatosis, steatohepatitis, or fibrosis?

• Hepatic steatosis (on imaging: ≥5% of hepatocytes; on biopsy: macrovesicular fat affecting ≥5% of cells)
• Plus at least 1 cardiometabolic risk factor (obesity, T2DM, dyslipidemia, or hypertension) - this is what defines MASLD vs. other forms of steatotic liver disease

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2. History Taking - What to Ask and Why

A. The First Question: Is It Really Non-Alcoholic?

• Ask about quantity, frequency, and pattern of alcohol use - using validated tools (AUDIT-C questionnaire)
• NAFLD is considered only when alcohol use is <20 g/day in women, <30 g/day in men (some guidelines use <20-40 g/day as the cutoff)
• Be tactful but direct - patients often underreport. Ask about weekends separately, ask about binge episodes, ask family members if needed
• If significant alcohol AND metabolic risk factors are both present, you cannot determine the dominant cause - both are assumed

B. Metabolic Risk Factors (Core History)

C. Drug History - Secondary Causes to Exclude

D. Surgical / GI History

• Prior bariatric surgery (jejunoileal bypass, biliopancreatic diversion - can cause NASH from SIBO and rapid weight loss)
• Extensive small bowel resection
• Total parenteral nutrition history

E. Symptoms - Most Patients Have None

• Most patients are asymptomatic (48-100% in series)
• Ask about: fatigue, malaise, vague right upper quadrant discomfort
• Absence of symptoms does not exclude NASH or even cirrhosis
• Ask about symptoms of portal hypertension in suspected advanced disease: abdominal distension (ascites), hematemesis, confusion (encephalopathy), edema

F. Risk Stratification Questions in History

"Red flag" features in history suggesting likely advanced disease:

• Age >50
• Obesity (especially BMI >35)
• Diabetes mellitus
• Hispanic ethnicity
• Hypertension
• Elevated ferritin (from labs)
• Known PNPLA3 risk allele (if genetic testing done)

G. Other Causes to Think About During History

• Viral hepatitis (HBV, HCV - particularly genotype 3 HCV itself can cause steatosis)
• Wilson's disease (young patient with liver disease - ask about neuropsychiatric symptoms)
• Celiac disease (associated with fatty liver)
• Hypothyroidism
• Lipodystrophy (partial or total)
• Glycogen storage diseases, abetalipoproteinemia (in appropriate clinical context)

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3. Physical Examination - What to Look For

A. General Inspection

B. Abdominal Examination

• Hepatomegaly - the most common physical sign; often smooth, non-tender enlargement
• Important caveat: difficult to appreciate in obese patients due to body habitus - don't be falsely reassured by inability to palpate the liver
• Splenomegaly - suggests portal hypertension from advanced disease/cirrhosis

C. Signs of Chronic Liver Disease (Late/Advanced Disease Only)

D. Cardiovascular Examination

• Blood pressure measurement - hypertension is a risk factor and associated condition
• Signs of metabolic syndrome (central obesity, BP)
• NAFLD patients have increased cardiovascular mortality - cardiovascular disease is the #1 killer in NAFLD overall, exceeding liver-related mortality (liver-related mortality overtakes CV only in NASH cirrhosis)

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4. Staging Systems - The Details

A. Histological Activity: The NAFLD Activity Score (NAS)

B. SAF Score (Steatosis-Activity-Fibrosis)

• Scores steatosis (S0-S3), activity (A0-A4, combining lobular inflammation + ballooning), and fibrosis (F0-F4) separately rather than adding them together
• This allows more granularity and is considered more reliable in routine clinical practice
• NASH-CRN system remains the regulatory gold standard for clinical trials

C. Fibrosis Staging - the Most Important Prognostic Factor

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5. Non-Invasive Staging - How to Stratify Without Biopsy

Step 1 - Initial Blood Tests (First-Line in Primary Care/Clinic)

FIB-4 = (Age × AST) / (Platelet count × √ALT)

NFS = -1.675 + (0.037 × age) + (0.094 × BMI) + (1.13 × IFG/diabetes [yes=1, no=0]) + (0.99 × AST/ALT ratio) - (0.013 × platelet count) - (0.66 × albumin)

Step 2 - Elastography (If FIB-4 Indeterminate)

• Non-invasive, office-based, measures liver stiffness in kPa
• AUROC ~0.93 for advanced fibrosis (cutoff ~9.9 kPa)
• Use XL probe in obese patients
• Also measures CAP (controlled attenuation parameter) for steatosis quantification simultaneously

• Most accurate non-invasive fibrosis assessment (superior to VCTE)
• Combined with MRI-PDFF for simultaneous steatosis quantification
• Disadvantage: higher cost, limited availability

Step 3 - Liver Biopsy (When Needed)

• FIB-4/NFS indeterminate AND elastography inconclusive
• Prior to starting pharmacological therapy
• Suspected competing or coexisting diagnosis
• High clinical suspicion of advanced disease with discordant non-invasive tests
• Before bariatric surgery if advanced liver disease suspected

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6. Lab Work-Up - What to Order and Why

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7. Imaging - What Each Modality Does

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8. The Diagnostic Algorithm (Practical Flow)

Patient presents with:
  - Incidental elevated ALT/AST, OR
  - Steatosis on imaging, OR
  - Metabolic syndrome evaluation

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Step 1: EXCLUDE ALCOHOL (>20-30g/day excludes NAFLD/MASLD)
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Step 2: EXCLUDE SECONDARY CAUSES
  (drugs, hepatitis B/C, Wilson's, hypothyroid, celiac)
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Step 3: CONFIRM STEATOSIS
  Ultrasound → if equivocal → MRI-PDFF
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Step 4: CONFIRM MASLD
  Steatosis + ≥1 cardiometabolic risk factor = MASLD
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Step 5: RISK-STRATIFY FIBROSIS (non-invasively first)
  FIB-4 → If low (<1.30): low risk, monitor
         → If indeterminate (1.30-2.67): FibroScan/MRE
         → If high (>2.67): refer hepatology
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Step 6: LIVER BIOPSY (selective)
  When non-invasive tests are indeterminate, conflicting,
  or biopsy will change management

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9. Key Pearls to Keep in Mind

1. Normal liver enzymes do NOT exclude NASH or cirrhosis - the entire histologic spectrum including cirrhosis can be present with normal ALT/AST
2. Absence of symptoms doesn't help - most patients with advanced disease are asymptomatic
3. Fibrosis stage predicts mortality, not NAS - a patient with NAS 6 but F0 has better prognosis than NAS 3 with F3
4. AST > ALT should make you suspect alcohol - in NAFLD it is consistently ALT > AST
5. Ferritin elevated ≠ hemochromatosis in NAFLD - it's secondary iron in Kupffer cells
6. ANA positivity (<1:320) in 25% of NAFLD - does not mean autoimmune hepatitis
7. PNPLA3 gene variant is the most important genetic risk factor for severity and HCC risk
8. As fibrosis progresses, steatosis decreases - a "burnt-out" NASH cirrhosis may have minimal fat on biopsy, making it appear cryptogenic
9. Cardiovascular disease kills more NAFLD patients than liver disease - always assess and manage CV risk
10. Hispanic ethnicity is independently associated with higher risk of advanced NAFLD

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• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 11th ed.
• Yamada's Textbook of Gastroenterology, 7th ed.
• EASL-EASD-EASO Clinical Practice Guidelines on MASLD, Journal of Hepatology 2024
• ACR Appropriateness Criteria: Cervical Radiculopathy 2024