UAMS P2 - Therapeutics 1 Exam 4 SG

Corresponding Tests for the Liver: Protein Synthesis Function

Albumin, PT/INR (clotting proteins)

Corresponding Tests for the Liver: Excretion in bile ducts and Drainage into Duodenum

Bilirubin, Alkaline Phosphatase (ALP), 5'-nucleotidase (5-NT), Gamma-glutamyl transpeptidase (GGT)

Corresponding Tests for the Liver: Hepatocellular injury

Aspartate aminotransferase (AST), alanine aminotransferase (ALT)

Corresponding Tests for the Liver: Detoxification

Ammonia (NH3)

______________________ is the major role of the liver

Protein Synthesis

Normal Albumin Range

4-5 g/dL

Symptoms of Hypoalbuminemia

Albumin < 2-2.5 g/dL, Peripheral Edema, Pulmonary Edema, Ascites

Causes of Hypoalbuminemia

Cirrhosis, Malabsorption/malnutrition, Protein loss (gut - enteropathy, kidney - nephrotic syndrome, skin - burns), Increased blood volume (large volume IV administration)

Normal Prothrombin Time (PT) Level

12.7-15.4 seconds

Normal International Normalized Ratio (INR) Range

0.9-1.1

A coagulation deficit leads to _________________ PT/INR

Increased

Hepatic impairment or Vitamin K deficiency can lead to ________________ PT/INR

Increased

What's the Likely Cause of the PT abnormality: Pt has Prolonged PT, Vitamin K is given and PT normalizes

Malabsorption, Malnutrition, Warfarin, Antibiotics

What's the Likely Cause of the PT abnormality: Pt has Prolonged PT, Vitamin K is given and PT remains elevated

Liver failure

Impairment of Protein Synthesis occurs from:

Cirrhosis - Chronic alcohol use - Chronic viral hepatitis Acute Liver Failure - Autoimmune hepatitis - Lethal toxin ingestion (tylenol, mushrooms)

High bleeding risk = ________________ PT/INR

High

______________ is a deficiency of the excretory function of the liver

Cholestatic Liver disease

Bile is stored ____________ and excreted into the ______________

gallbladder; duodenum

Failure of excretory function of the Liver can lead to:

Jaundice (from bilirubin), Scleral icterus (from bilirubin), Pruritis (from bile salts), Xanthomas (from lipid deposit in skin)

Normal Total bilirubin

0.3-1.3 mg/dL

____________ is a product from the breakdown of RBCs (heme pigments)

Bilirubin

Elevated bilirubin causes ____________________ when bilirubin is > __________

jaundice and icterus; 2-4 mg/dL

Indirect Hyperbilirubinemia Characteristics

70% of Total Bilirubin is Indirect (high levels of indirect bilirubin), Increased breakdown of RBCs (hemolysis), Reduced transport of bilirubin into the hepatocyte (Probenecid), Reduced hepatic conversion to direct bilirubin (Rifampin, Gilbert Syndrome, Cringler-Najjar Syndrome)

Direct Hyperbilirubinemia Characteristics

>50% of total bilirubin is direct, Sign of cholestatic liver disease, Hepatic disease that interferes with secretion and clearance

Normal ALP (Alkaline Phosphatase) Levels

33-96 units/L

Reasons ALP would be elevated:

Increased osteoblastic acitivity during growth, Bile accumulation increasing ALP production

5-Nucleotidase (5NT) Range

0-11 units/L

An Increase in ALP with Normal 5NT suggests _______________

a non-hepatic cause to ALP increase

GGT (Gamma-glutamyl Transpeptidase) Normal levels

9-58 units/L

____________ is a biliary excretory enzyme and is elevated in cholestatic disease (Answer with Acronym)

GGT

GGT is likely elevated in ________________

Alcohol abuse, pancreatic disease, MI, COPD, hyperthyroidism, RA, DM

Name the Potential Diagnosis: ALP: Slight Increase GGT and 5NT: Normal AST/ALT: Normal

Pregnancy or Non-hepatic cause

Name the Potential Diagnosis: ALP: Moderate Increase GGT and 5NT: Large Increase AST/ALT: Normal or Minimal Increase

Cholestatic Diseases

Name the Potential Diagnosis: ALP: Mild Increase GGT and 5NT: Mild Increase AST/ALT: Large Increase

Hepatocellular Disease

Normal Aspartate Aminotransferase (AST) Level

12-38 units/L

Normal Alanine Aminotransferase (ALT) Level

7-41 units/L

____________ assesses hepatocellular injury

Transaminases (AST and ALT)

Extremely high levels of Transaminases (> 1000) are Associated with:

Acute viral hepatitis, Severe drug toxicity, Ischemic hepatitis

For diagnosis of Alcohol Hepatitis

AST:ALT Ratio (AST 2x ALT generally and rarely > 300-400) GGT is also elevated

Factors that Increase AST/ALT Ratio

Medications: - Acetaminophen - Levodopa - Methyldopa - Erthromycin Vigorous exercise (2-3x in males)

Factors that Decrease AST/ALT Ratio

Dialysis (by half)

AST Elevation Likely from:

Alcohol, Steatohepatitis, Cirrhosis, Hemolysis, Myopathy, Thyroid, Exercise

ALT Elevation Likely from:

Viral hepatitis, Steatohepatitis, Ischemic Hepatitis, Autoimmune hepatitis, Medications/Toxins

Normal Ammonia (NH3) Level

19-60 mcg/dL

High levels of Ammonia (>250) are generally associated with

Hepatic encephalopathy (HE)

Ammonia Levels generally depict the liver's ability to ________________

Clear blood toxins (its a normal waste product in the blood removed by the liver)

Physical Signs of Liver Disease

Jaundice, Xanthoma, Spider angioma, Ascites, Palmar Erythema

What is Asterixis

"Hand ""flapping"" tremor; Often seen in hepatic encephalopathy; Also caused by: - Hypoxic encephalopathy - Uremic encephalopathy - Electrolyte Distrubances - Phenytoin - Carbamazepine - Opioid Overdose"

In Child-Pugh Score, what factors are considered?

Total Bilirubin, Albumin, INR, Ascites, Encephalopathy

In Model for End-Stage Liver Disease (MELD) Score, what factors are considered?

Total bilirubin, INR, Creatine, Hyponatremia

Increasing presence of MASLD (Metabolic Dysfunction-Associated Steatoic Liver Disease) is associated with increasing rates of ________________

obesity

What Screening Score is used for MASLD and what does it mean?

FIB4: used to identify probability of advanced fibrosis

Risk Factors of MASLD (Metabolic Dysfunction-Associated Steatoic LIver Disease)

Obesity, T2DM, Dyslipidemia, Obstructive Sleep Apnea, Cardiovascular Disease, Chronic Kidney Disease

MASLD Non-Pharm Treatment:

Alcohol Abstinence, Weight Loss (Bariatric surgery is appropriate except in decompensated cirrhosis), Exercise

MASLD Pharm Treatment:

Moderate to High Intensity Statin + Other Hypolipemic agent

Agents with Clinical Benefits of Steatosis

Vitamin E, Pioglitazone, Liraglutide, Semaglutide, resmetirom (Rezdiffra)

Agents with Reduced Clinical Benefits of Steatosis

Tirzepatide, SGLT-2

Agents with Clinical Benefits of Fibrosis

resmetirom (Rezdiffra)

Rezdiffra (resmetirom) ADEs

Pruritis, N/D, Increased ALT/AST

resmetirom (Rezdiffra) is used only for

noncirrhotic patients only

Upper Limit of Drinking for Men and Women

Men: 2 drink/24hrs Women: 1drink/24hrs (There is no safe level of alcohol use)

Alcohol Use Disorder is a chronic ________________

disease

Medications FDA approved for AUD treatment

Naltrexone, Acamprosate

Medications Recommended for AUD treatment in Alcohol Associated Liver Disease

Acamprosate, Baclofen

Single most important factor in improving survival in ALD

Abstinence

Naltrexone use in Alcohol Use Disorder

Opioid Receptor Antagonist, Can be initiated when patient is drinking, Avoid in liver failure or if patient is on opioids

Acamprosate use in Alcohol Use Disorder

666mg TID, No metabolism, Renally excreted, NMDA Receptor Antagonist, Abstinence required at initiation, Avoid in Renal impairment

Gabapentin use in Alcohol Use Disorder

Modulates GABA activity, dose adjustment in renal dysfunction, Monitor for increased sedation

Baclofen use in Alcohol Use Disorder

30-60 mg/day, Hepatic Metabolism, Renally eliminated, GABA-b Receptor agonist, Safe in ALD and cirrhosis

Topiramate use in Alcohol Use Disorder

GABA action augmentation, Not recommended in ALD

Agents that are protective against the development of ALD

Coffee

Risk factors for the development of ALD

Alcohol use above upper limit, Pattern consumption of alcohol, Presence of other conditions, Smoking cigarettes, Female Sex, Genetics, Increased BMI

Types of Alcohol-Associated Liver Disease

Alcohol-Associated Steatosis, Alcoholic Hepatitis, Alcohol-Associated Cirrhosis

Alcohol Hepatitis Labs Albumin: PT/INR: Bilirubin: GGT: AST/ALT:

Albumin: Decreased PT/INR: Increased Bilirubin: Increased GGT: Increased AST/ALT: Increased (>1.5 ratio)

MDF (Maddrey Discriminant Function)

MDF = 4.6 * (PT - Normal PT) + Total Bilirubin

Elegibility for Treatment of Alcoholic Hepatitis

MDF >= 32 or MELD > 20, Ultrasound to exclude other causes of Jaundice, Screen for Infection

Contraindications to Treatment for Alcoholic Hepatitis

Uncontrolled Infection; AKI with SCr > 2.5' Uncontrolled upper GI bleed; Concomitant HBV, TB, DILI, Pancreatitis, HIV; Multiorgan Failure or Shock

What is the purpose of Lille Model?

Predicts Steroid responders and Non Responders; Taken 7 days after initial treatment of Corticosteroid < 0.45 = 6-month Survival of 85%, continue treatment for 28 days then taper > 0.45 = 6-month Survival of 25%, stop corticosteroid

Initial Treatment of Alcoholic Hepatitis

Corticosteroids; Prednisolone preferred since it's active form; Prednisolone 40mg QD x7 days then Lille Model: - < 0.45 = Continue for 28 days then taper - > 0.45 = Stop Prednisolone

Corticosteroids Monitoring

BP, Glucose, Weight Gain, Fluid Retention, Infection, Bone Mineral Density, GI effects (GERD)

Treatment for Alcoholic Hepatitis

Corticosteroids, Enteral Nutrition - Increased calorie intake of >21 kcal/kg/day N-acetylcysteine (NAC) 40mg/day IV - hepatoprotective - improves 30 day survival Lifelong Alcohol Abstinence

When to Refer Alcoholic Hepatitis

Ineligible for treatment or non-responders should be referred for liver transplant or palliative care

MetALD is associated with

MASLD + Increased Alcohol Intake

________________ is a chronic cholestatic, autoimmune disease of the intrahepatic bile duct

Primarily Biliary Cholangitis (PBC)

Lab Abnormalities associated with Primary Biliary Cholangitis

Increased ALP Slight Increase in AST/ALT ratio Increase in Antimitochondrial antibody (AMA)

Symptoms of Primary Biliary Cholangitis

Fatigue, Pruritis, Abdominal Pain

Risk Factors for Primary Biliary Cholangitis

Genetic, Environmental, UTI, Reproductive hormone replacement, Nail polish, Past Cigarette Smoking

Treatment For Primary Biliary Cholangitis (PBC)

1st: Ursodiol (13-15 mg/kd/day PO) 2nd: Obeticholic Acid (5mg/day PO) Off Label: Fibrates (fenofibrate 160mg QD)

Ursodiol MOA for PBC

Choleretic, cytoprotective, anti-inflammatory, and immunomodulatory

Obeticholic Acid MOA for PBC

FXR agonist modulating bile acids and having anti-inflammatory and antifibrotic effects

Ursodiol ADEs

N/V/D

Obeticholic Acid ADEs

Abdominal Pain

Obeticholic Acid BBW

Contraindicated in patients with current or history of decompensated cirrhosis or portal hypertension

Fibrates ADEs

Myalgias, Heartburn, Decreased GFR

Fibrates Dosing Considerations

Renally dose adjusted and use in caution in patients with liver disease

2 Additional meds for PBC that is used in combination with Ursodiol

elafibranor (Iqirvo) - 80mg PO QD, seladelpar (Livdelzi) - 10mg PO QD

elafibranor (Iqirvo) MOA

Selective PPAR alpha and delta agonist decreasing bile acid synthesis, modulating bile acid output, and promoting bile acid transport

elafibranor (Iqirvo) ADEs

N/V/D/Abdominal Pain, Weight Gain, Fracture, Myalgias

elafibranor (Iqirvo) Drug Interactions

CYP3A4 Substrators - Iqirvo can Decrease Concentrations Statins - Iqirvo can enhance toxic effects Hormonal Contraception - Iqirvo can decrease concentrations Rifampin - Can decrease the concentration of Iqirvo

seladelpar (Livdelzi) MOA

PPAR delta agonist decreasing bile acid synthesis