Drug-Induced Liver Injury (DILI)

• Dr. Katrina Nguyen can be contacted at [email protected]

Acronyms

• DILD stands for Drug-Induced Liver Disease
• DILI stands for Drug-Induced Liver Injury
• NAFLD stands for Non-alcoholic Fatty Liver Disease
• MASLD stands for Metabolic dysfunctions-associated steatotic liver disease
• NASH stands for Non-alcoholic Steatohepatitis
• MASH stands for Metabolic dysfunctions-associated steatohepatitis

Learning Objectives

• Review the pathophysiology of Drug-Induced Liver Injury (DILI)
• Review the pathophysiology of MASLD and MASH
• Review non-pharmacotherapy and pharmacotherapy for the above topics if applicable
• Perform Hepatic Dose-Adjustment in End-Stage Liver Disease (ESLD)
• Compare PELD and MELD

Prevalence of Drug-Induced Liver Injury (DILI)

• DILI accounts for 11% – 13% of all cases of acute liver failure in the United States
• As of 01-01-23, the US population was 334,233,854 according to census.gov
• 11% of the US population would be 36,765,723 people
• DILI accounts for 20% of acute liver failure in pediatric populations
• Approximately 75% of DILI cases require liver transplantation for patient survival
• 60% of liver transplantations are caused by acetaminophen, isoniazid, antiepileptics, and antibiotics according to the United Network for Organ Sharing (UNOS)

Introduction to DILI

• The range of drugs that can cause DILI is extensive
• DILI in clinical settings commonly involves alcohol, antibiotics, antiepileptics, acetaminophen, and herbals
• DILI can be fatal and can have debilitating outcomes
• The liver's function affects every other organ system, as it is exposed to every substance absorbed from the gut and every injected substance entering the bloodstream
• The liver's normal functioning enzymes and processes can cause a drug to become toxic through bioactivation
• DILI has many different clinical presentations, like idiosyncratic reactions, allergic hepatitis, toxic hepatitis, chronic active toxic hepatitis, toxic cirrhosis, and liver vascular disorders
• Monitoring for DILI must be customized to the kind of drug and the patient's potential risk factors

Mechanisms of DILI

• Stimulation of Autoimmunity
• Idiosyncratic reactions
• Disruption of Calcium Homeostasis and Cell Membrane Injury
• Cytochrome P450 Enzymes as Agents of Liver Damage
• Liver Transport Proteins and Liver Cell Communities as Agents of Liver Damage
• Stimulation of Apoptosis
• Mitochondrial Injury
• Liver Neoplastic Disease
• Mechanisms of DILI are diverse, involving many phases of biotransformation and are susceptible to genetic polymorphism

Stimulation of Autoimmunity

• This can manifest as fulminant presentations
• Causative agents include: Halothane, sulfamethoxazole, carbamazepine, nevirapine, fluoroquinolones, and anti-tumor necrosis factor (TNF) alpha inhibitors
• Mechanism: Enzyme-drug complexes migrate to the hepatic cell surface and form neoantigens, leading to antibody-mediated cytotoxicity or direct cellular toxicity
• The liver is host to all cells involved in the innate immune response, including Kupffer cells (macrophages from reticuloendothelial cells)
• Reticuloendothelial cells (porous frame) around hepatocytes constantly monitor and communicate via cytokines to stimulate or regulate an immune response
• Neoantigens serve as targets for cytolytic attack by killer T cells

Autoimmune-mediated Chronic Active Hepatitis

• This involves periods of symptomatic hepatitis followed by periods of recuperation, repeating months later
• This is a progressive disease with a high mortality rate and is more common in females than males
• Causative agents include: Dantrolene, isoniazid, phenytoin, nitrofurantoin, trazodone, and methyldopa
• The mechanism involves drugs forming anti-organelle antibodies
• Antinuclear antibodies (ANA) appear in most patients' labs

Idiosyncratic Reactions - RARE

• Allergic Reactions are responsible for 37% of all idiosyncratic DILI
  • Includes a hypersensitivity response: Fever, rash, eosinophilia, and granulomas
  • Is a Dose-related and characterized by a Short latency period of less than 1 month
  • Causes Rapid recurrence of hepatotoxicity upon re-exposure to offending agent
  • Causative agents: Minocycline, nitrofurantoin, phenytoin, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, ACE-I, and allopurinol
  • Mechanism involves genetic polymorphism of Human Leukocyte Antigen (HLA) phenotypes that mediate patient's susceptibility and severity of inflammatory reactions in the liver
    • HLA type A33:01, HLA type B35:01, HLA type B14:02, and HLA type C08:021 have this effect
    • HLA type B*5701: flucloxacillin and abacavir have this effect
• Nonallergic Reactions
  • Presents with normal Liver Function Tests (LFTs) for at least 6 months, then suddenly develops hepatotoxicity
  • Lacks hypersensitivity response
  • Characterized by a Long latency period of several months
  • May be independent or dose-related
  • Not associated with rapid reinjury when rechallenge
  • Causative agents: Amiodarone, isoniazid, Ketoconazole
  • Mechanism: Unknown

Disruption of Calcium Homeostasis and Cell Membrane Injury

• Causative agents: Lovastatin, venlafaxine, and phalloidin (mushrooms)
• Mechanism: Drug-induced damage to cellular proteins involved with calcium homeostasis leads to:
  • An influx of intracellular Calcium causing a decline in ATP levels and disruption of the actin fibril assembly
  • Blebbing of the cell membrane, rupture, and cell lysis

Cytochrome P450 Enzymes as Agents of Liver Damage

• These reactions take place in the smooth endoplasmic reticulum (SER) of hepatocytes, leading to their dispersion throughout the cell
• Causative agents: acetaminophen, furosemide, and diclofenac
• Mechanism: Most hepatocellular injuries involve the production of high-energy reactive metabolites by the CYP450 system
  • These reactive metabolites can covalently bond with transport proteins, enzymes, and nucleic acids
  • In acute hepatotoxicity, these enzyme-drug complexes can cause cell injury or cell lysis
  • The complexes that form with DNA can induce neoplasia
• Genetic differences can affect this process, particularly single nucleotide polymorphisms (SNP) that code for slow-reacting variants of CYP450 versus SNPs that code for very fast-reacting variants

Liver Transport Proteins and Liver Cell Communities as Agents of Liver Damage

• Genetics and the innate roles of several proteins and cell types in the liver can accelerate or protect the liver from damage
• Efflux membrane transport proteins actively pump drugs and other xenobiotics into the hepatocyte for processing and elimination from the body
• Canalicular membrane efflux transporters pump metabolites and some drugs into the bile canaliculus
• Single Nucleotide Polymorphisms (SNPs) that code for various bile salt export pumps (BSEP), especially variants of ATP-binding cassette transporters, are associated with rare congenital liver diseases and cholestasis during pregnancy, leading to a higher risk for cholestatic liver injury
  • Causative agents: Cyclosporine A, sulindac, rifamycin, and glimepiride inhibit bile salt export pumps (BSEP)
• Multi-drug and toxin extrusion exchanger 2 (MATE2) in the liver excrete cationic drugs; several SNPs modify MATE2 function, and causative agents are : metformin, oxaliplatin, acyclovir, and fexofenadine

Stimulation of Apoptosis

• Apoptosis has a distinct pattern of cell lysis characterized by cell shrinkage and fragmentation of nuclear chromatin
• Mechanism: Apoptotic pathways are triggered by interactions between death ligands tumor necrosis factor and Fas ligand & death receptors tumor necrosis factor receptor 1 and Fas receptor
  • These interactions activate caspases (cleave cellular proteins)
  • All the above mechanisms leads to cell death

Mitochondrial Injury

• Causative agents:
  • Mitochondrial injury by inhibiting beta-oxidation: aspirin, valproic acid, and tetracycline
  • Disruption of oxidative phosphorylation: amiodarone
• Mechanism: Drugs that impair mitochondrial structure, function, or DNA synthesis can disrupt beta-oxidation of lipids and oxidative energy production within the hepatocyte
• Acute disease leads to microvesicular steatosis
• Chronic disease leads to macrovesicular steatosis

Liver Neoplastic Disease

• Hepatic tumors due to drug therapy are usually benign and remit when the drug is discontinued
• These tumors/lesions are linked to long-term exposure to the offending agents
• Causative agents include: Androgens, estrogens, and other hormonal-related agents
• Polyvinyl chloride exposure induces angiosarcoma and hepatic cancer in exposed workers in as few as 3 years of high-quality exposure
• Mechanism: Carcinoma- and sarcoma-like lesions develop due to drug therapy, though the tumors are benign

Centrilobular Necrosis (Acetaminophen)

• Cell damage occurs in hepatocytes closest to the central vein of the liver due to the production of a toxic metabolite where damage spreads outward from the middle of a lobe
• Acetaminophen overdose bioactivated to a toxic intermediate NAPQI that has high affinity for sulfhydryl groups
• Glutathione, a tripeptide stored in the liver, is a readily available source of sulfhydryl groups
• Glutathione detoxifies NAPQI; if glutathione is depleted, NAPQI reacts directly with hepatocytes, leading to necrosis
• N-acetylcysteine is used as treatment for acetaminophen (APAP) overdose, replenishing sulfhydryl groups and halting necrosis
• Symptoms include nausea and vomiting without elevation of common liver enzymes (until 40–50 hours after ingestion)

Alcohol-related Liver Injury

• Ethanol is what commonly caused steatonecrotic changes in the liver
• Alcohol is converted to acetaldehyde which increases fatty acids production
• The hepatocyte becomes engorged with microvesicular fat, leading to alcoholic fatty liver
• Alcoholic fatty liver reduces hepatocytes' ability to respond to stress, bypassing normal apoptosis and increasing the necrocytolysis rate

Phospholipidosis

• Mechanism: Accumulation of phospholipids instead of fatty acids in hepatocytes, creating engorgement of the lysosomal bodies of the hepatocyte
• Amiodarone and its metabolites cause phospholipidosis as they are stored in the liver for several months after discontinuation of therapy

Generalized Hepatocellular Necrosis

• Acetylation is the main pathway and involves isoniazid
• Acetylated into acetylisoniazid
• Hydrolyzed to acetylhydrazine
• Directly toxic to hepatocyte proteins
• Rapid acetylators detoxify acetylhydrazine rapidly
• Isoniazid metabolites are directly toxic to the hepatocytes

Additional Mechanisms of Drug-Induced Liver Injury

• Methotrexate causes periportal fibrosis in patients with hepatotoxicity
• The bioactivated metabolite produced by CYP450 causes the lesion, which is more common in psoriasis and arthritis.
• Vitamin A, or retinol, is normally stored in the liver
• High doses over long periods cause hypertrophy and fibrosis, leading to hepatomegaly, ascites, portal hypertension, gingivitis, and dry skin. Alcohol accelerates injury by competing with retinol for aldehyde dehydrogenase.
• Tetracycline (high dose, IV, > 1.5g/day)) can cause Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic dysfunction-Associated Steatohepatitis (MASH), characterized by large vesicles of fat diffused throughout the liver.

Drugs That Can Cause Harm to the Liver

• Includes: Dantrolene, Isoniazid, Phenytoin, Nitrofurantoin, Trazodone, Methyldopa, Minocycline, Bactrim, Testosterone, Carbamazepine, Acetaminophen, Furosemide, Diclofenac, Aspirin, Valproic acid, Tetracycline, Amiodarone, ACE inhibitors, Ketoconazole, and Estrogen

Traditional & Herbal Medicines

• Traditional and herbal medicines contribute to 14 out of 132 cases of DILI
• Examples include: Comfrey tea, Jinbuhuan or chaparral capsules containing grease wood leaves, Pennyroyal oil, Margosa oil, Clove oil, Body building agents (e.g., Anabolic steroids), Weight loss products, and Depression/joint care products combined with Chinese herbs

Three types of DILI

• Hepatocellular damage
• Cholestatic damage
• Mixed hepatocellular cholestatic damage

Hepatocellular Injury

• Fulminant hepatitis has a 20% survival rate with supportive care; if jaundice is present, the mortality rate is 10%
• Causative agents: Acarbose, allopurinol, fluoxetine, and losartan
• Most hepatocellular injury happens within 1 year of drug initiation
• Significant elevations occur in serum aminotransferases before elevations in total bilirubin (TBL) and alkaline phosphatase (Alk Phos)
• Hy's Law defines hepatocellular injury as Alanine Transaminase (ALT) > 3 times the Upper Normal Limit (UNL) + Total Bilirubin (TBL) > 2 times the UNL without significant elevation in Alkaline Phosphatase (Alk Phos)
• The FDA recommends evaluating the ratio of ALT to Alk Phos
  • R = (measured ALT/UNL of ALT) / (measured Alk Phos/UNL of Alk Phos); where R > 5 for hepatocellular injury

Assessment: Liver Enzymes

• The pattern of liver enzyme changes can identify liver injury and the type of liver damage present
• Liver biopsy is used in rare, severe cases to categorize DILI by assessing the histology pattern changes
• The first indicator of injury is the elevation of enzymes, like:
• Alanine Aminotransferase (ALT)
• Aspartate Aminotransferase (AST)
• Alkaline Phosphatase (Alk Phos)
• Total Bilirubin (TBL)
• Other liver enzymes and lab tests include: Liver kidney microsomal auto-antibodies (LKM-1) which are indicative of autoimmune hepatitis, and micro-RNA, which are elevated in steatosis and ballooning inflammation

Autoimmune-related liver injury

• Includes autoimmune hepatocellular injury which presents with fever and elevations in antinuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), Liver Kidney Microsomal type 1 (LKM-1), and gamma globulins
  • Characterized by rapid onset, < 2 months from drug initiation
  • If early diagnosis, it may respond to high dose glucocorticoid treatment (must be careful as it can worsen fatty liver disease)
• Cholestatic injury is more common in people over age 60 and in males
  • Marked by Alk Phos elevation primarily where Alk Phos > 3 times the Upper Normal Limit (UNL)
  • Related medications are: erythromycin, amoxicillin-clavulanic acid, carbamazepine, an IV form of vitamin E, long-term and high-dose estrogen

Liver Enzymes Comparison

• Alkaline phosphatase( Alk Phos, AP): Elevated in necrotic, cholestatic, and chronic conditions
• 5'-Nucleotidase (5-NC, 5NC): Elevated in necrotic, cholestatic, and chronic conditions
• γ-Glutamyltransferase (GGT, GGTP): Elevated in necrotic, cholestatic, and chronic conditions
• Aspartate aminotransferase (AST, SGOT): Highly elevated in necrotic conditions, mildly elevated in cholestatic conditions, and elevated in chronic conditions
• Alanine aminotransferase (ALT, SGPT): Highly elevated in necrotic conditions, mildly elevated in cholestatic conditions, and elevated in chronic conditions
• Lactate dehydrogenase (LDH): Highly elevated in necrotic conditions, mildly elevated in cholestatic conditions, and mildly elevated in chronic conditions

Assessment: Liver Severity

• Serum bilirubin (indicator of hepatic lesions) at high concentrations indicate poor survival
• Prothrombin time (>40 seconds) indicates poor survival
• Jaundice (prolonged) is a strong indicator for transplantation
• Encephalopathy is a strong indicator for transplantation
• Lactate dehydrogenase (LDH) plays an important role in making energy; an increase indicates tissue damage
• Elevated serum creatinine
• Low arterial pH
• These values give a picture of the liver's condition, not its functions

Assessment: Liver Functions

• Serum protein (albumin or transferrin) decreases as liver functions decrease It should be noted that overhydration and starvation can decrease serum protein, however
• Albumin levels < 2.8 g/dL is associated with a high mortality rate
• Changes in prothrombin time reported as INR (international normalized ratio) occur earlier than changes to albumin or transferrin and is a good indicator of acute liver failure
  • Responses to vitamin K are used as a differential between hepatic or extrahepatic disease
• Normal INR = 1; an increase in INR means blood is thin and it takes longer to clot which indicates liver disease with the liver not making the clotting factors for blood to clot normally

Child-Pugh Score

• It is a scoring system of the degree of liver failure in patients with cirrhosis

• It is used to predict mortality or survival rate of cirrhosis patients

  • A (Mild impairment) with a score of 5-6 has a One-year survival of 100% and a Two-year survival of 85%
  • B (Moderate impairment) with a score of 7-9 has a One-year survival of 80% and a Two-year survival of 60%
  • C (Severe impairment) with a score of 10-15 has a One-year survival of 45% and a Two-year survival of 35%

Child-Pugh Score Calculation also referred to as Child-Turcotte-Pugh (CTP) score

• To calculate:
• Use Total points to score Class A, B or C
• Factor 1: Total bilirubin - A-1=< 34 umol/L, B-2=34-50 umol/L, C-3=> 50 umol/L
• Factor 2: Serum albumin - A-1=> 35 g/L, B-2=28-35 g/L, C-3=< 28 g/L
• Factor 3: International normalized ratio (INR) - A-1=< 1.7, B-2=1.71-2.30, C-3=> 2.30
• Factor 4: Ascites - A-1=None, B-2=Mild, C-3=Moderate to Severe
• Factor 5: Hepatic encephalopathy - A-1=None, B-2=Grade I - II (or suppressed with medication), C-3=Grade III – IV (or refractory)

Other measurements of liver health: Child-Pugh vs. MELD/PELD

• MELD score = Model for End-Stage Liver Disease score
• Prognosis scoring system used to predict 3-month mortality
• PELD score = Pediatric End-Stage Liver Disease score
• Is a pediatric version of PELD
• Is a numeric scale for transplant candidates in younger than 12
• Is used as a scoring system for liver cirrhosis severity and transplant planning

MELD ranges from 6-40 and involves those twelve years old and older

• To calculate, you need
  • Date of birth (Age)
  • Bilirubin (mg/dL)
  • INR
  • Serum Sodium (mEq/L)
  • Serum Creatinine (mg/dL)
    • Had dialysis at least twice within the past week OR continuous veno-venous hemodialysis (CVVHD) ≥ 24 hours within the past week --> Serum creatinine automatically set to 4.0 mg/dL
    • Serum Creatinine > 4.0 mg/dL will default to 4mg/dL
• Those with a MELD Score ≥ 10, must refer to hepatologist or liver transplant center

PELD

• PELD is only for ages less than 12 years old
• To calculate, you need
  • Date Added to the Waiting List
  • Date of birth (Age)
  • Gender
  • Bilirubin (mg/dL)
  • INR
  • Serum Albumin (g/dL)
  • Height (ft,in or cm)
  • Weight (lbs or kg)
  • History of growth failure (UNOS Growth Failure Chart based on gender, height, and weight)
• UNOS stands for United Network for Organ Sharing

When to use MELD/PELD?

• If you're interested in more information, contact the Organ Procurement and Transplantation Network (OPTN) at https://optn.transplant.hrsa.gov
• MELD shows how much a patient needs a liver transplant
• The higher the MELD score, the more urgent need for a liver transplant
• MELD score is recalculated often to determine patients' place on the waiting list registry
• If your MELD score is:
  • Under 10: It will be recalculated once a year
  • 11-18: It will be recalculated every 3 months
  • 19-24: It will be recalculated once a month
  • 25 or higher: It will be recalculated every week
• PELD is the pediatric version of MELD for use in pediatric patients who are less than 12 years old

Liver Transplants in the United States

• Data from OPTN reports that in 2022: 9,528 liver transplants, 25,499 kidney transplants, 4,111 heart transplants
• Data from OPTN reports that in 2012: 6,256 liver transplants, 16,487 kidney transplants, 2,378 heart transplants

New Nomenclature

• As of November 2023 AASLD Practice Guidance, NAFLD NASH will be referred to as:
  • SLD = Steatotic Liver Disease is the overall term to include various etiologies of steatosis
  • NAFLD is now called Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) Patients has hepatic steatosis and at least 1 of 5 cardiometabolic risk factors (BMI, glucose, blood pressure, triglycerides, and HDL)
  • MetALD – Metabolic dysfunction-Associated Steatotic Liver Disease with alcohol use includes patients with MASLD and consume greater than amounts of alcohol per week (Female = 140g/week and Male = 210g/week)
  • NASH is now called Metabolic dysfunction-Associated Steatohepatitis (MASH) which is defined as steatohepatitis and is retained due to important pathophysiological concept
  • Cryptogenic SLD: patients with no metabolic parameters and no known cause

MASLD and MASH Definitions:

• MASLD:
  • Macrovesicular steatosis (≥5% hepatocytes. May have mild inflammation. No alcohol use. No alternative cause of steatosis.
• MASH:
  • MASLD including the presence of inflammation and cellular injury (ballooning). With or without fibrosis.
• Cirrhosis:
  • Bands of fibrous septa leading to; Formation of cirrhotic nodules
• NASH-related cirrhosis is now the leading indicator of liver transplantation in women and those age>65

MASLD/MASH Prevalence

• 30-40% of adults in the US have MASLD.
• 3-12% of adults in the US have MASH.
• Almost 10% of children (2-19 years old) have MASLD.
• 20% of people with MASLD have MASH.
• MASLD and MASH can impact all races and ethnicities.
• MASLD and MASH are more common in Hispanics and non-Hispanic whites.
• MASLD and MASH are more common in patients with T2DM and/or obesity.

Etiology of MASLD /MASH

• Suspected due to unknown cause:
• Overweight or obese (especially with large waist size)
• Insulin resistance
• T2DM
• Abnormal lipid panel (high Triglycerides, high Total Cholesterol, high LDL Cholesterol, low HDL Cholesterol)
• High blood pressure
• Metabolic syndrome (MetS), also known as cardiometabolic risk factors:
  • Body Mass Index greater than or equal to 25 kg/m² [23 Asian] OR Large waist circumference of greater than 94 cm [Male] or 80 cm [Female]
• Elevated fasting blood sugar greater than or equal to 100 mg/dL OR 2-hr postprandial greater than or equal to 140mg/dL OR Hemoglobin A1c greater than or equal to 5.7% OR T2DM OR treatment for T2DM
• Blood Pressure greater than or equal to 130/85mmHg OR specific antihypertensive drug treatment
• High Triglycerides greater than or equal to 150 mg/dL OR lipid lowering treatment
• Low HDL less than or equal to 40 mg/dL [Male] and 50 mg/dL [Female] OR lipid lowering treatment
• Additional etiologies and connections include Polycystic Ovarian Syndrome (PCOS) and/or exposure to environmental toxins or medicines.

Diagnosis of MASLD /MASH:

• Medical history involves:
  • Alcohol intake to differentiate, with heavy use defined as alcohol consumption consisting of greater than: Male - More than 4 drinks/day or more than 14 drinks/week [≥ 60 g/day(Male)] or: Female: more than 3 drinks/day or more than 7 drinks/week [≥ 40 g/ day(Female)].
  • High sugar and starch diet, along with a lack of physical activity
• Tests involved are:
  • Liver biopsy showing: Steatosis in greater than or equal to 5% of hepatocytes coupled with both ballooning and lobular inflammation in the absence of any other contributory factors such as excessive alcohol consumption.
  • Non-alcoholic Fatty Liver Disease Fibrosis Score (NFS) or Fibrosis 4 score (FIB-4) index are clinically useful to identify MASLD patients with a high chance of having bridging fibrosis (stage 3) or cirrhosis (stage 4). -NFS helps detect liver fibrosis [based on BMI, hyperglycemia, platelet count, albumin, and Aspartate Aminotransferase (AST) / Alanine Aminotransferase (ALT) ratio.]
  • FIB-4 index is calculated using platelet count, age, Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) - If FIB-4 is less than 1.3, then primary care and reassessment is required periodically every 1 to 2 years for those with pre-Diabetes Mellitus (DM), T2DM, or those with 2 or more Q1 metabolic risk factors). - If FIB-4 is greater than or equal to 1.3, then a secondary assessment such as a Vibration-Controlled Transient Elastrography or Enhanced Liver Fibrosis test and/ or referral is required.
• Imaging helps doctors see and quantify hepatic steatosis (HS) and involves: Ultrasound (U/S) and Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF).
• Vibration-Controlled Transient Elastrography and Magnetic Resonance Elastography are more efficient to identify advanced fibrosis and involves:
  • Vibration-Controlled Transient Elastrography (FibroScan, stage 3 and above) measures the stiffness of the liver
  • Magnetic Resonance Elastography (MRE) (stage 2 and above) is great at identifying a various degree of fibrosis in patients with Metabolic Associated Steatohepatitis (MASH).
• Liver biopsy (Gold Standard) but is invasive, expensive, has high sampling error, and risks complications such as pain, bleeding, and/or death

Non-Pharmacotherapy Treatment of MASLD /MASH

• Should consider Bariatric surgery if eligible due to improvements to NASH and reductions in mortality from CV disease and malignancy
• Weight loss through sustainable lifestyle improvements is the gold standard, with:
  • Milder disease: modest weight loss impactful
  • Weight loss of 3-5% improves steatosis
  • Greater weight loss of with more than 10% weight loss gradually over 1 year improves MASH and fibrosis with more than 10% rapid weight loss worsens existing MASH
• Maintain and improve: Healthy food choices (green leafy vegetables, fruits, low fat, low carb, DASH diet) with low amounts of saturated fats, refined carbs, and sugar-sweetened beverages
• High fructose diets can increase risk for MASLD, MASH, and advanced fibrosis
• Consume roughly 3 cups of coffee on a daily basis which reduce the risk of Metabolic Associated Steatohepatitis (MASH) and or cirrhosis independently of caffeine content
• Abstain from alcohol in patients especially with clinically significant hepatic fibrosis from stage F2 to F4
• Exercise often independently regardless of weight loss aids in hepatic metabolism and cardiometabolic system

Pharmacotherapy

• Rezdiffra™ (resmetirom)
• The only FDA-approved as of March 2024 to treat MASH by resolving steatohepatitis and even improve fibrosis symptoms
• It's MOA works through modulating the Thyroid Hormone Receptor-Beta Agonist to reduce the amount of intrahepatic triglycerides in the liver.
  • Clopidogrel should be modulated with a resmetirom adjustment of 80mg daily if the individual weights more than 100 kg or 60mg daily if they weigh less than 100kg.
• Also works with Statin’s although doctors are instructed to maximize at the lower ends such as Rosuvastatin and Simvastatin at 20mg daily while increasing Atorvastatin and Pravastatin to 40mg daily.
• The medicine comes with a few adverse events that should be known such as Diarrhea, nausea, and pruritus
• Is black box warned for gallbladder disease in individuals with liver disease already
• Has many contraindications when pregnant such as maternal drop in T4, T3, and TSH levels
• The medicine in addition has no available information on whether the medicine can transmit through breast milk
• Requires regular visits to monitor Liver Function Test (LFT), liver and gallbladder checks, thyroid function test, and lipid panel check

Non FDA Approved and Off-label Treatments:

• Semaglutide is sometimes leveraged for T2Dm and Obesity benefits in helping cardiovascular system and improving MASH
• Actos is leveraged to improve liver histology but is regulated to only diabetes patients with MASH

Vitamin E

• Is known as rrr-alpha-tocopherol, doctors advise 800 IU day in order to see help to the liver, nondiabetics benefit greatly from aggressively controlling histology due to it significantly improving steatosis, inflammation, ballooning, and resolution of steatohepatitis.
• Long term can cause cancer and hemorrhagic stroke at more than 400 IU of usage
• Supposedly, it prevents the propagation of free radicals therefore reducing oxidative stress from Reactive oxygen species
• Current clinical trials can show the following are non-beneficial: Semaglutide, Pioglitazone, and Vit E

Other potential options: Table 6 on 2023 AASLD Guidance*

• See chart for: https://journals.lww.com/hep/Fulltext/2023/05000/AASLD_Practice_Guidance_on_the_clinical_assessment.31.aspx

Drugs in the Pipeline for MASH:

• Obeticholic acid (OCA) is in phase III: a modified bile acid that is a farnesoid X receptor (FXR) agonist
• Selonsertib (phase III): a small molecule inhibitor of apoptosis signal-regulating kinase I (ASK)
• Emricasan (phase II): a small molecule caspase inhibitor
• Bristol-Myers Squibb (BMS)-985036: pegylated analogue of human fibroblast growth factor 21
• Elafibranor (phase III) with Genfit
• Cenicriviroc (phase II) with Tobira Therapeutics, Inc.