6 - Alcoholic and Nonalcoholic Fatty Liver Disease Flashcards
Primary place of lipid metabolism
Liver
What leads to fatty changes?
“Stressors”
What are the two categories of Fatty Liver?
Alcoholic
Non-Alcoholic
Secondary Steatosis - Fatty Liver
Alcohol
Overnutrition (Obesity, metabolic syndrome)
Starvation
TPN (Total parenteral nutrition)
Drugs (Amiodarone, methotrexate, tamoxifen, steroids)
Infections (HIV, HCV)
Celiac Disease
Genetic Causes (Abetalipoproteinemia, Wilson’s)
Alcohol-Induced Steatosis
(+/-)Alcoholic Hepatitis
Fibrosis
Cirrhosis
Non-Alcohol-Induced Steatosis
(+/-)Non-alcoholic Steatohepatitis
Fibrosis
Cirrhosis
Spectrum of Alcoholic Liver Disease
Alcoholic Fatty Liver Disease
Fibrosis
Alcoholic Hepatitis
Cirrhosis
Cutoff for how much fat the liver can handle as “normal”
5% of volume as fat
CDC definition of “moderate drinking”
2 drinks per day for men
1 drink per day for women
Risk factors for ALD
Amount of alcohol ingested:
Non-linear
Drinking outside of mealtime increases risk by 2.7 fold
Syngergistic relationship between viral hepatitis and alcohol in terms of advancing liver disease
How many grams in a standard drink?
12oz beer
8oz malt liquor
5oz wine
1.5oz distilled spirits
Risk of cirrhosis increases (men)
> 60 - 80g/day for at least 10 years
Risk of cirrhosis increases (women)
> 20g/day for at least 10 years
CAGE Criteria
Tried to CUT down
People ANNOYED you by criticizing drinking
Felt GUILTY about drinking
Needed an EYE OPENER
Score of 2 is clinically significant
Damage done in alcoholic hepatitis
NAD accepts proton from alcohol dehydrogenase
Forms acetaldehyde
Free-reactive species of acetaldehyde forms adducts
Increases ROS formation
Increases NADH/NAD+ ratio
Acetaldehyde build up causes majority of damage
CYP2E1 Pathway in Alcohol Metabolism
ROS species increases
Outbalances reduction
Inflammation ensues
LPS’s Role in Alcohol-Induced Liver Injury
Ethanol promotes translocation of LPS
Lumen of small intestine to Portal vein to liver
In Kupffer cell, LPS stimulates activation through promotion of cytokine and ROS release
Alcoholic Hepatitis
Clinical syndrome of acute jaundice and liver failure
Occurs after DECADES of alcohol abuse
Inflammatory
Fibrosis MAYBE but generally not cirrhotic
Scariest consequence: Portal hypertension (due to microvascular occlusion secondary to hepatic swelling)
Alcoholic Hepatitis - Presentation
Rapid onset of jaundice Fever Ascites Proximal muscle loss Encephalopathy Liver is enlarged & tender
Alcoholic Hepatitis - Physical Exam
Signs of Chronic Alcohol Use:
Parotid enlargement
Dupuytren’s Contracture
Gynecomastia (relative depletion of testosterone)
Signs of Severe Liver Disease: Visible veins across the abdominal wall Edema Ascites Spider telangiectasia
Alcoholic Hepatitis - Histo
Ballooned Hepatocytes
Mallory bodies (alcoholic hyaline) surrounded by PMNs
Amorphous eosinophilic inclusion bodies
Large fat globules (macro-steatosis) in hepatocytes
Alcoholic Hepatitis - Labs
Elevation of serum aminotransferases (hallmark of hepatitis)
AST/ALT ratio > 2
Maddrey Discriminant Function:
Poor prognosis >= 32 (very high risk of dying, 30 - 50 % 28 day mortality)
Lille Model:
Helps predict mortality to guide therapy
Alcoholic Hepatitis - Treatment
Abstinence (though risk of progressing to cirrhosis remains)
Treat nutritional deficiencies
Steroids (1st line):
Prednisolone 40 mg/day for one month, then discontinue or taper over 3w
Appropes for those with MDF >= 32
15 - 30% risk reduction in short term (28d) mortality in early studies, 4% in more recent studies
Alcoholic Hepatitis - Other treatments
Anti-cytokine therapy:
Mitigates the effects of dysregulatd cytokines (TNF-α)
Pentoxifylline:
Inhibits production of TNF-α and other cytokines
STOPAH trial showed NO mortality benefit
Transplantation and CIrrhosis
Longstanding alcohol use and/or alcoholic hepatitis leads to fibrosis/cirrhosis
Alcoholic hepatitis and active drinking are absolute contraindications to consideration for liver transplantation
Require at least 6 months abstinence from drinking prior to transplant evaluation
Nonalcoholic Fatty Liver Disease
Entire spectrum of fatty liver disease without significant alcohol use, ranges from fatty liver to steatohepatitis to cirrhosis
Nonalcoholic Fatty Liver (NAFL)
Hepatic steatosis
No evidence of hepatocellular injury (ballooning)
No fibrosis
Nonalcoholic Steatohepatitis (NASH)
Hepatic steatosis
Inflammation
Hepatocyte injury (ballooning)
(+/-) fibrosis
NASH Cirrhosis
Cirrhosis
Previous histological evidence of steatosis or steatohepatitis
Metabolic Syndrome - Definition
Abdominal obesity
Hypertension
Diabetes
Dyslipidemia
Metabolic Syndrome - Associated wtih
Impaired glucose metabolism
Impaired fatty acid utilization
Dyslipidemia
Metabolic Syndrome and NASH
Present in 88% with NASH
54% with NAFLD without NASH
Metabolic Syndrome - Hepatic Manifestation Venn Diagram
Insulin Resistance
Obesity
Hyperlipidemia
How many American Adults are overweight (BMI>25)
2/3
From 1960 - 2000 What happened to obesity prevalence?
DOUBLED
Cost of obesity epidemic
$117 billion
NAFLD - Epidemiology
Most common liver diseases in Western, industrialized countries
20 - 40% of general population
More common in men
Majority of cases occur in men between 40 and 60
Hispanics > Caucasians > African Americans
NASH - Two Hit Pathogenesis
First Hit:
Fat accumulation
Discrepancy between influx/synthesis of hepatic lipids and β-oxidation and export leading to buildup of triglycerides
Second Hit: Oxidative stress Lipid peroxidation Release of cytokines (TNF-α) Adipocyte derived hormones
Main driver for fibrosis
Insulin resistance
Leads to cytokines, inflammatory signaling, stellate cell activation, apoptosis, mitochondrial injury, oxidative stress, etc
NAFLD Pathology
Macrovesicular steatosis
Hepatocyte balooning
Lobular inflammation (Mixed leukocytes)
Mallory bodies (eosinophilic inclusions)
Perivenular & sinusoidal fibrosis - Scarring around central vein
(NOT PRESENT IN ALCOHOLIC)
Presentation
Asymptomatic - Normal Liver Chemistries
Elevated transaminases
Fibrosis
Cirrhosis
Picture of Pediatric Fatty Liver
Hepatic steatosis
Portal & lobular inflammation
Improper nutrition
Cardiometabolic risk
Lipid associated (leptin resistance, visceral obesity, etc)
NAFLD Comorbidities
Obesity Type 2 DM Glucose Intolerance Dyslipidemia Metabolic Syndrome
OSA Hypothyroid Hypopituitary PCOS Hypogonad
NAFLD Diagnosis
AST & ALT elevation (90% of patients)
AST/ALT:
1 in ASH
No study outside of biopsy can differentiate between simple steatosis & NASH
NAFLD Progression
Progression from Stage 0 to Stage 4
NAFLD (100%)
Fibrosis Progression (33%)
Rapid Fibrosis Progression (20%)
Annual fibrosis progression rate
- 07 stages for NAFL
- 14 stages for NASH
NASH and End Stage Liver Disease
Prevalence of cirrhosis ranges from 3 - 15%
Once cirrhosis sets in, nothing can reverse it
Only cure for decompensated cirrhosis is transplant
Histologically learn to tell the difference between
Fatty Liver
NASH
NASH with Fibrosis
Cirrhosis
How do we diagnose NASH?
LIVER BIOPSY
NASH vs ASH
38 - 50% of patients with ASH progress to cirrhosis (7 years)
8 - 26% of NASH patients progress to cirrhosis
Lower survival rates in ASH: 5 year (38% vs. 67% in NASH) 10 year (15% vs. 59% in NASH)
NASH & Cirrhosis
Prevalence of obesity increased among cryptogenic cirrhotics
DM prevalence high with cirrhosis
How many projected patients have NASH?
25 million
How many transplants were performed for NASH in 2002
160
Treatment of NAFLD
Mainstay - Lifestyle Intervention:
Diet
Behavior modification
Physical activity (Exercise reduces steatosis even without weight loss)
Weight loss:
Medical
Surgical
Pharmacotherapy
Insulin Sensitizers PPAR-α/δ agonists FXR agonists Antioxidants Caspase Inhibitors Antifibrotics
Current Recommendations - Biopsy proven NASH, nondiabetic, noncirrhotic
Vitamin E 800 IU/d
Current Recommendations - Biopsy proven NASH, diabetic
Pioglitazone (Safety data in NASH limited)
Current Recommendations - NAFLD + Hypertriglyceridemia
Omega-3 Fatty Acids
