6 - Alcoholic and Nonalcoholic Fatty Liver Disease Flashcards by Mikey Montalbano

Primary place of lipid metabolism

Liver

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What leads to fatty changes?

“Stressors”

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What are the two categories of Fatty Liver?

Alcoholic

Non-Alcoholic

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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)

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Alcohol-Induced Steatosis

(+/-)Alcoholic Hepatitis
Fibrosis
Cirrhosis

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Non-Alcohol-Induced Steatosis

(+/-)Non-alcoholic Steatohepatitis
Fibrosis
Cirrhosis

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Spectrum of Alcoholic Liver Disease

Alcoholic Fatty Liver Disease
Fibrosis
Alcoholic Hepatitis
Cirrhosis

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Cutoff for how much fat the liver can handle as “normal”

5% of volume as fat

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CDC definition of “moderate drinking”

2 drinks per day for men

1 drink per day for women

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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

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How many grams in a standard drink?

12oz beer
8oz malt liquor
5oz wine
1.5oz distilled spirits

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Risk of cirrhosis increases (men)

> 60 - 80g/day for at least 10 years

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Risk of cirrhosis increases (women)

> 20g/day for at least 10 years

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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

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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

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CYP2E1 Pathway in Alcohol Metabolism

ROS species increases
Outbalances reduction
Inflammation ensues

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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

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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)

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Alcoholic Hepatitis - Presentation

Rapid onset of jaundice
Fever
Ascites
Proximal muscle loss
Encephalopathy
Liver is enlarged &amp; tender

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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

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Alcoholic Hepatitis - Histo

Ballooned Hepatocytes
Mallory bodies (alcoholic hyaline) surrounded by PMNs
Amorphous eosinophilic inclusion bodies
Large fat globules (macro-steatosis) in hepatocytes

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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

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Alcoholic Hepatitis - Treatment

Study These Flashcards

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

Study These Flashcards

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 0. 07 stages for NAFL 0. 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

6 - Alcoholic and Nonalcoholic Fatty Liver Disease Flashcards

(57 cards)