NAFLD AND AFLD (DR.

LASALA) 1
NON-ALCOHOLIC FATTY LIVER DISEASE SIGNIFICANT ALCOHOL INTAKE
- Evidence of hepatic steatosis (HS), either by imaging or histology - >21 standard drinks per week in men and >14 standard drinks per
- Lak of secondary causes of hepatic fat accumulation such as week in women over a 2 year period preceding baseline liver
o Significant alcohol consumption histology
o Long term use of a steatogenic medication - According to the NIAA, a standard alcoholic drink is any drink that
o Monogenic hereditary disorders contains about 14g of pure alcohol. Unfortunately, the definition
- Diagnosed via imaging or histology, which is more definitive of significant alcohol consumption in published NAFLD literature
- Fatty liver without cases of hepatic steatosis has been inconsistent
o significant alcohol consumption
CLINICAL MANIFESTATION:
STAGES Initial presentation of NAFLD
- Non-alcoholic fatty liver disease – NAFLD - No complication – 78%
- Non-alcoholic Steatohepatitis - HCC – 12%
- Non-alcoholic Cirrhosis (>60% of cryptogenic) - Cirrhosis – 10%

DEFINITION OF TERMS NAFLD encompasses a spectrum of varying disease Severity

- NAFLD – encompasses the entire spectrum of FLD in individuals - Simple steatosis – steatic hepatitis fibrosis  Cirrhosis  HCC
without significant alcohol consumption, ranging from fatty liver - Any stage can escalate to HCC
to SH to cirrhosis o HCC – does not always follow cirrhosis, but may develop even
- NAFL – presence of 5% HS without evidence of hepatocellular from steatosis
injury in the form of ballooning of the hepatocytes or evidence of
fibrosis. The risk of progression to cirrhosis and liver failure to Two HIT concept
considered minimal - 1st hit: lipid accumulation
- NASH – presence of 5% HS with inflammation and hepatocyte o Increased FFA  lipid accumulation primarily from obesity
injury (ballooning) with or without fibrosis. This an progress into and insulin resistance  lipids incite oxidative stress,
cirrhosis, liver failure, and rarely after cancer inflammation  hepatosteatosis
- NASH cirrhosis – presence of cirrhosis with currEnt or previous - 2nd hit: oxidative stress, cytokine activation
histological evidence of steatosis or SH
- Cryptogenic cirrhosis – presence of cirrhosis with no obvious Environmental
etiology. Patients with cryptogenic cirrhosis re heavily enriched - Dietary factors
with metabolic risk factors such as obesity and MetS - Food intake
- Physical activity
RISK FACTORS - Gut microflora
Common Condition w/ Established Association Genetic
- Obesity – most important risk factor - Oxidative stress
o BMI >30 kg/m2 - Immune related
- T2DM - Metabolic
- Dyslipidemia
- Met syndrome This is a continuum
- PCOS – most are overweight - Normal
Other conditions
- Hypothyroidism NATURAL HISTORY OF FATTY LIVER
- OSA Simple steatosis NASH Severe NASH with
- Hypothyroidism fibrosis
- Hypogonadism Fat deposition of Ballooning, 75% go in for
- Pancreaticoduodenal resection >5% Inflammation, +/- cirrhosis
- Psoriasis Fibrosis
Age, sex, ethnicity?? Benign course Worse prognosis 5 yr survival 67%
- Age – not established 3% develop cirrhosis 30% develop cirrhosis 10 yr survival 45%
- Sex – males (more common) but not established Can be reversed if w/o
o Drinkers fibrosis
- Ethnicity – more on Caucasians probably due to Western diet Each Perpetuating the Other
- NAFLD – hepatic component of metabolic syndrome
METABOLIC SYNDROME What is the implication?
Presence of 3 or more - If we find one… look for the other
- Waist circumference >102cm in men or >88cm in women
- TG level >=150mg/dL Risk factors
- HDL cholesterol level <40mg/dL in men and <50mg/dL in women - Obesity – most important
- Systolic blood pressure >=130 mmHg or diastolic pressure - High TG
>=85mmHg - Diabetes
- Fasting plasma glucose level >=110mg/dL

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NAFLD AND AFLD (DR. LASALA) 2

Clinical Presentation Laboratory Abnormalities

- Asymptomatic – most - Anorexia/Nausea - ALT/AST – 2-4x elevated
- Routine blood tests - >90% are obese - AST: ALT ratio (De Ritis ratio) <1
- Increased liver enzymes - USD: Fatty liver o Reversal – alcoholic liver
- Enlarged liver (1/3) - Acanthosis nigricans - AKP slight increase in 1/3
- RUQ/periumbilical pain - DM, HTN, Dyslipidemia - Dyslipidemia – Increased TG, low HDL
- Fatigue/Malaise - OSAS, Snoring - FBG and PPBG increased
o Fatigue – most - Bun and Crea – normal
common presentation - Albumin and PT: normal
if symptomatic - Low ANA+ <1 in 320
- Increased serum ferritin
- Increased iron saturation
- AST:ALT Ratio > if Cirrhosis sets in

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NAFLD AND AFLD (DR. LASALA) 3
DIAGNOSTIC TESTS FOR FATTY LIVER MRI, MRS, CT Results are variable and Tests are costly,
Test Sensitivity Specificity Remarks scan +/- not well verified less available
Histology, Gold Cannot Significant contrast cannot distinguish
liver biopsy standard reliably variability enhancement steatosis and
distinguish between fibrosis or
between pathologists NASH/ASH or
ASH and reading of the stage disease, and
NASH same sample; a re insensitive if
highly experienced there is <33%
hepatopathologist
is best Biopsy – reliably identify fatty liver but it is costly
Liver enzymes Low Low AST/ALT usually - risk of bleeding in patients with cirrhosis (inadequate
<1.0; values may production of coagulation factors)
be normal - Positive yield may be low
Ultrasound Limited Limited Insensitive unless - Steatosis – macrovesicular fat accumulation
steatosis >33% - Steatohepatitis: ballooning degeneration
operator USD: Most common imaging but interpretation is subjection and
dependent may yield false (-)

Treatment - Above mentioned deficit - Protein should comprise about

- the most important management is weight loss enables weight loss 0.5-1kg 20% of total calories
- Exercise per week - Meal intake: It is
- Lifestyle modification recommended in consume 4-5
- Caloric restriction meals per day; breaks between
- Bariatric surgery or BIB procedure meals should not exceed 2-3h
- Last meal should be consumed
Clinically meaningful endpoints at least 3h before sleeping
1. Prevent progression or achieve regression/reversal - Meals should be consumed
o NAFL>>>NASH slowly
o NAFLD>>>Significant fibrosis/ cirrhosis - It is important to finish eating
o Bridging fibrosis/cirrhosis >>>> cirrhosis complications when the patient does not feel
o NAFLD>>> HCC/death satiety; signal of satiety is felt
2. Improve CV outcomes usually 15 minutes after the
end of consumption
Diet in Obese/NAFLD patients - Energy requirement should be tailored to personal needs. Physical
Energy content: Nutrients in diet activity, height, and weights should be considered
- 1000—1200 kcal per day for - Carbohydrate should comprise - Keto diet is not recommended
obese women 40-50% of total calories o high incidence of ketosis
- 1200-1600 kcal per day for - Fat should comprise <=30% of - Mediterranean diet is high in UFA, which is good
obese men total calories (saturated fatty
- Energy deficit should be acids >7% and <10% of total
between 500-1000 kcal per calories)
day

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NAFLD AND AFLD (DR. LASALA) 4
WEIGHT LOSS THROUGH LIFESTYLE MODIFICATION IN NAFLD health-care health-care weapon in
- Everyone should memorize this provider provider treating NASH;
Weight Outcome among patients Sustain weightloss an enthusias-
loss achieving weight os at >1 year tic support
>10% Fibrosis regression (45% of <10% group is very
patients) helpful
>7% NASH resolution (64-90% of 18% 2. Diabetes One of the key Generally Essential to
patients) control risk factors; available control if
>5% Ballooning and inflammation 30% well- present
improvement (41-100%) recognized
>.3% Steatosis improvement (35- Not reportEd help problem
100% of patients) 3. Lipid- Becoming Require Important to
Fibrous Elastography lowering more widely resources for control if
- special USD probe that can tell the degree of steatosis agents available w/ medications, present
- Grade 0 – no fibrosis but with some steatosis good and training of
- Reaching the level of F4 – already early cirrhotic liver cheaper health-care
Level 3 – generics; providers
limited Availability Feasibility Remarks dietary
resources changes will
1. Weight loss, Limited Limited Lifestyle also help if
diet, exercise, training training changes are hyperlipidemia
education required for required for the single is present
most effective

PHARMACOLOGIC DIET
- There is no single effective drug of NAFLD = give combination ALCOHOLIC LIVER DISEASE
- Metformin/Pioglitazones - 75% of US population, with a 7% incidence of alcoholism
o Peglitazone – some patients gain weight after some time - Accounts for app 100,000 deaths/year
- Vitamin E – 800 IU /day o >20% deaths due to cirrhosis
o Anti-oxidant effect  decreased progression of NASH - Men>women; non-blacks>blacks
- Glucagon-like Peptide-1 analogue (liraglutide) o Though blacks have a higher rate of cirrhosis
- Statins: Atorvastatin/Rosuvastatin - Abuse presents serious public health and social problems, all of
o lower LDL, increase HDL which are preventable
- TG elevation: fenofibrates
- Ursodeoxycholic acids/omega-3 FA ALCOHOLIC LIVER DISEASE
- Liver injury attributed to abuse
CONCLUSION - American drink without serious consequences
- Main cause of increased liver enzymes - May begin to develop after a “threshold” dose of alcohol has been
- Spectrum of disease – NAFLD NASH  Cirrhosis  HCC consumed
- Insulin resistance, MS are the key pathogenic features - Daily intake:
- DM, TG, Non-fatty abdominal obesity, increasing age o Men:
- Always look for DM, TG, CVD if you see fatty liver  Four 12 ounce beers
- Presently the management is to improve IR, TG, Dm  Four glasses of wine
- It is a marker of CV Risks: Rx, improve insulin sensitivity  Four ounces of hard liquor
- Modify underlying metabolic risk factors – diet, exercise o Women: ½ dose for men
- Scoring system is available. No biopsy
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NAFLD AND AFLD (DR. LASALA) 5
- Fatty liver is usually asymptomatic
o On evaluation hepatosplenomegaly is present in 70% of
patients and there may be mild abnormalities in
transaminases
 Splenomegaly = anemia and thrombocytopenia
o Synthetic function is poor – coagulopathy, hypoalbuminemia,
increased globulin levels
- Patients w/ alcoholic hepatitis may also be asymptomatic
o Hospitalized patients usually have jaundice and hepatomegaly
and may exhibit ascites, encephalopathy, and fever
depending on the severity of their disease

Fatty Liver/Steatosis
- abnormal accumulation of fat in the parenchymal cells of the liver
and can occur w/in hours of significant alcohol intake
TYPES OF ALD - In the majority of patients (90%) it is associated with palpable liver
3 types of liver disease enlargement
Fatty Liver - Fat deposits accumulate predominantly in the central and mid-
- *Reversible with abstinence [missing content] zonal areas of the liver (zone 3 and 2) and may be macrovesicular
Alcoholic Hepatitis (large droplets) or microvesicular (small droplets)
- An acute form of alcohol-induced liver injury that occurs with the - Steatosis is indistinguishable from NAFLD, Drug-induced, AFLP
consumption of a large quantity of alcohol over a prolonged - Fatty liver is a completely reversible lesion, assuming the patient
period abstains from alcohol
Cirrhosis Microscopy
- Involves replacement of normal hepatic parenchyma with - Hepatic steatosis
extensive thick bands of fibrous tissue and regenerative nodules, - Microvesicular lipid droplets in hepatocytes, become macro-
which results in the clinical manifestations of portal hypertension vesicular globules
and liver failure - Large, soft, yellow, greasy liver
Alcoholic Hepatitis Cirrhosis - Non-fibrous initially
*Alcoholic hepatitis can range *Fibrosis of nodules in the liver - Severe liver dysfunction unusual
in severity from asymptomatic parenchyma - Reversible with abstinence
derangement of *Compensated cirrhosis: Steatohepatitis
biochemistries to liver failure delayed presentation of cirrhotic - Missing content
and death changes or liver function tests Microscopy
*Consumption of large may be normal even with - Inflammation and centrilobular necrosis in alcoholic liver
quantity of alcohol over a long fibrotic liver Fibrosis
period - Fibrosis (Or scar formation) first begins in the pericentral zone
*Can be asymptomatic to then progresses if disease continues. Alcoholic cirrhosis is of the
presenting w/ S/Sx of liver micronodular type
failure and death - The normal lobular architecture is obscured and central veins are
*May or may not revert w/ difficult to locate. The amount of fat is variable and alcoholic
abstinence hepatitis may or may not be present
- Continuing necrosis a nd fibrosis result in the progression from
Types of Alcoholic liver disease micro- to macronodular pattern. This progression is accompanied
Type Histologic specificity Prognosis Reversible by a reduction in steatosis in end-stage liver disease. Cirrhosis is
for alcoholic cause not reversible
Fatty liver No Excellent Yes
Alcoholic No Variable Variable PHYSICAL EXAM
hepatitis Constitutional *Fever
Cirrhosis No Guarded Generally no Skin *Spider angioma
- Guarded – In cirrhosis, some patients still have acceptable liver *Parotid and lacrimal gland enlargement
function  compensated cirrhosis *Primary erythema
1. Stages of histologically detectable liver damage often overlap *Jaundice
2. Some never progress, regardless of the patient’s continued (Decreased body hair
ethanol abuse *Gynecomastia
Musculoskeletal *Dupuytren’s contracture
SYMPTOMS OF PATIENTS WITH ALD *Clubbing
- Asymptomatic to end-stage liver diseases with portal *Muscle wasting
hypertension, jaundice and encephalopathy Genitourinary *Testicular atrophy
- Gastro: nausea, dry retching, diarrhea, anorexia, and abdominal Abdomen *Hepatomegaly or small shrunken liver
pain *Splenomegaly
- Consequences of alcoholism: accidents, violent behavior, *Ascites
depression, tremors, poor work performance, or social disruptions *Hepatic tenderness
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NAFLD AND AFLD (DR. LASALA) 6
Neurologic *Asterexis - Liver biopsy may be useful to confirm the diagnosis, rule out other
*Confusion, stupor diseases, and prognosticate
LABORATORY EXAMINATION - Patients with severe alcoholic hepatitis should be considered for
Liver synthetic fxn *Hyperbilirubinemia (usually conjugated) enrollment in clinical trials
*Prolonged prothrombin time - Corticosteroids treatment can be used in patients with DF>32 or
*Hypoalbuminemia MELD >21 without contraindication to glucocorticoid
Liver enzyme levels *AST and ALT levels elevated usually <500 - Current evidence do not support the need for pentoxifylline
U/L (AST/ALT ratio – 2:1) treatment
Hematologic *Anemia - Patients with alcoholic cirrhosis should be evaluated for liver
*Leukocytosis or neutropenia transplantation
*Thrombocytopenia
*Increased serum globulin levels
Metabolic *Elevated blood ammonia level
*Hyperglycemia
*Respiratory alkalosis
*Hypomagnesemia
*Hypophosphatemia
*Hyponatremia
*Hypokalemia

Treatment
- ABSTINENCE!!! – most important
- Referral to center for support
- Hospitalization – with complications
o Portal hypertension, variceal bleeding
o Encephalopathy
o Dyspnea
o Decompensated liver cirrhosis
Treatment Routine use Potential
Recommended Benefits
Abstinence Yes Survival
Nutritional support Yes Survival,
laboratory
Corticosteroids Yes Survival
Pentoxifylline No Suival, less renal
failure
Propylthiouracil No No
Infliximab No No
Colchicine No No
Insulin, glucagon No No
Calcium channel No No
blocker
Vitamin E No No
5-adenosyl-L- No No
methionine
Silymarin (milk No No
thistle)
Liver transplantation Consider (for 5 year survival –
decompensated 70%
cirrhosis)
- Pentoxifylline – TNF inhibitor
- Silymarin – only FDA approved supplement for the liver (liver lover
boy)
- Nutritional support for PEM and muscle wasting

Conclusion
- All patients should be screened for alcoholic liver disease
- Abstinence is the cornerstone of treatment of alcoholic liver
disease
- Alcoholic liver disease is a heterogenous disease
- The diagnosis of alcoholic liver disease requires a detailed patient
history with supportive laboratory and imaging studies

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