NAFLD and Alcoholic Liver Disease

Question 1

Epidemiology of NAFLD

Answer 1

-Commonest cause of liver disease worldwide (25% and rising)
=Leading indication for liver transplant in women/ 2nd overall
-Strongly linked to obesity and T2 DM
=Genetic susceptibility contributes PNPLA3 variant

Question 2

Describe NAFLD as a spectrum of disease

Answer 2

-Healthy
-Isolated steatosis (NAFL)
-Steatohepatitis (NASH)- activity and scarring (steatosis and ballooning for activity)
-Fibrosis/ cirrhosis
-Hepatocellular carcinoma

Question 3

4 stages of fibrosis

Answer 3

1. Periportal or perisinusoidal
2. Periportal AND perisinusoidal
3. Bridging fibrosis (bands between vascular structures)
4. Cirrhosis (thick bands form nodules)

Question 4

Why is degree of liver fibrosis important?

Answer 4

-Main predictor for clinical outcomes in fatty liver disease

Question 5

Pathogenesis of NASH

Answer 5

-Substrate overload
-Free fatty acids
=Lipolysis of TG in adipose tissue
=De novo lipogenesis (excess sugars converted to fatty acids)
-Lipotoxic lipids affect liver cell behaviour via multiple mechanisms= trigger cell injury, inflammation, fibrosis

Question 6

What is included in full liver screen?

Answer 6

-Viral hepatitis serology (HBV, HCV)
-Ferritin and transferrin
-LFTs
-Ceruloplasmin (copper binding protein in Wilson’s)
-Alpha 1 antitrypsin
-Lipids
-Autoimmune- liver autoantibodies
-Immunoglobulins

-Liver ultrasound: hyperechoic, <20-30% liver fat does not detect changes

Question 7

Clinical features of NAFLD

Answer 7

-Fatigue
-Mild RUQ pain
-Metabolic syndrome (T2DM, dyslipidaemia, high BP)
-Unexplained liver enzyme abnormalities
-Incidental finding of fatty liver on imaging

Question 8

Findings from clinical examination in NAFLD

Answer 8

-Central obesity
=May have normal BMI (10% ‘lean’ NAFLD)
-High BP, xanthelasma, hepatomegaly, cirrhosis?

Question 9

Routine blood tests in NAFLD

Answer 9

-Transaminase levels may be misleading
=Can be normal even in advanced/ progressive disease
=Up to 80% NAFLD have normal ALT
=AST>ALT suggests fibrosis/ cirrhosis, increased AST associated with disease progression
=Often increased GGT and alk phos

-Mildly positive autoantibodies (ANA, ASMA) in 10-30%

-Abnormal iron indices (particularly ferritin)
=Dysmetabolic hyperfferritinaemia
=Doesn’t indicate genetic haemochromatosis

Question 10

Diagnostic goals of NAFLD

Answer 10

1. Exclude other aetiologies (may coexist with NAFLD)
2. Identify risk factors for NASH
3. Assess and quantify fibrosis
   =Serum and imaging biomarkers
   =Role of liver biopsy?
4. Identify and treat co-morbidities
   =Obesity, diabetes, hypertension, cholesterol

Question 11

What diseases need to be excluded in NAFLD patient?

Answer 11

-Alcoholism= common, father with alcoholism
-Autoimmune liver disease= mother with hypothyroidism
-Wilsons disease= devasting if not treated
-Viral hepatitis, haemochromatosis

Question 12

Examples of other causes of fatty liver

Answer 12

-Excessive alcohol consumption
-Malnutrition
-Medications (amiodarone, valproate, tamoxifen, methotrexate, HAART)
-Parenteral nutrition

Question 13

Examples of other liver diseases that can present with steatosis

Answer 13

-Chronic hepatitis C (genotype 3)
-Wilson’s disease
-Metabolic abnormalities (lipodystrophy, lysosomal acid lipase deficiency)

Question 14

Clinical predictors of NASH in patients with NAFLD

Answer 14

-Advanced age
-Gender (postmenopausal= accelerated)
-Race (increased in Hispanic/ Asians, decreased in black)
-HTN, central obesity, dyslipidaemia (increased TG, decreased LDL), insulin resistance/ DM
-AST/ALT ratio >1, low platelets
-Persitsently raised ALT
-Serum ferritin >1.5x ULN

Question 15

Examples of simple serum-based fibrosis tests

Answer 15

-AST/ALT ratio
-BARD (BMI, AST/ALT Ratio, diabetes)
-NAFLD Fibrosis Score/ NFS (diabetes, AST/ALT, age, BMI, platelets, albumin)
-APRI (AST, platelets)
-FIB-4 (ALT, AST, platelets, age)

Question 16

Compelx tests for fibrosis

Answer 16

Detect BIOLOGICAL markers
-ELF (hyaluronic acid, PNIIIP, TIMP-1)
-NIS4 (miR-34a, alpha-2 macroglobulin, YKL-40, HbA1c)

-Fibroscan/ transient elastography (fat 290-300, >15 stiffness cirrhosis, above 7 abnormal)

Question 17

Treatment for NAFLD

Answer 17

-Weight loss
=>3% improved steatosis
=>7% NASH resolution
=>10% improved fibrosis

-Bariatric surgery (malabsorptive or restrictive?)
-Focus on healthy eating habits
-Encourage increased activity
-Limit alcohol (safe level), increase coffee (protective), avoid drugs that promote steatohepatitis

Question 18

Pharmacological targets for NAFLD medications

Answer 18

-Targets relating to insulin resistance and/or lipid metabolism
-Targets related to lipotoxicity and oxidative stress
-Targets related to inflammation and immune activation
-Targets related to cell death (apoptosis and necrosis)
-Targets related to fibrogenesis and collagen turnover

Question 19

Co-morbidities in NAFLD

Answer 19

-Cardiovascular disease
=Independent risk factor
=25% deaths in NAFLD due to CVD
-Obstructive sleep apnoea
=May worsen NAFLD
-Chronic kidney disease
=Risk factor for CKD

Question 20

Spectrum of alcohol related liver disease

Answer 20

-Normal
-Acute alcoholic hepatitis (severe exposure, 10-35%)
-Steatosis (90-100%= fatty change and perivenular fibrosis)
-Cirrhosis (8-20%)

Question 21

Describe acute alcoholic hepatitis

Answer 21

-Clinical syndrome characterised by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use
-Short-term mortality >30% with severe AAH
-Direct toxic effects on hepatocytes (oxidative stress), indirect gut effects (endotoxins, leaky gut, bacterial toxins travel to gut)
-Obesity potentiates severity of AH
-Genetic variants (PBPLA3)

Question 22

Clinical history in AH

Answer 22

-Heavy alcohol intake, typically for years- women twice as likely to develop hepatotoxicity with lower amounts and shorter duration of alcohol use compared to men
-Recent (<1 month) onset or worsening of jaundice
-Exclusion of other liver disease, biliary obstruction, HCC
->70% underlying cirrhosis (acute on chronic)

Question 23

Physical signs of AH

Answer 23

-Fever (25%)
-Hepatomegaly (tender) (75%)
-Jaundice (60%)
-Ascites (30-60%)
-Hepatic bruit (rare)

Question 24

Classical laboratory findings in AH

Answer 24

-Cholestasis (bilirubin >80)
-Leucocytosis (neutrophilia)
-AST: ALT >2
-Moderate raised AST (<300)

Question 25

Causes of very high transaminases

Answer 25

-Ischaemia
-Drugs (paracetamol)
-Viruses
-Acute biliary obstruction (gallstone)

Question 26

Assessing severity of AAH

Answer 26

-Maddrey’s discriminant function (DF)
=4.6 x (patient’s PT- control PT) + bilirubin/17
=Value >32 indicates severe AH (20-30% mortality with 1 month)
-MELD, Lile model, Glasgow score (age, WCC, urea, PT ratio INR, Bilirubin- >9 predicts poor outcome)

Question 27

General management of AAH

Answer 27

-Abstinence from alcohol
-Nutrition
=Enteral feeding may be required
=Pabrinex
=Phosphate, magnesium, zinc
-Correct coagulation- vitamin K
-Treat alcohol withdrawal (diazepam)
-Aggressive screen for infection
=Blood, urine, chest, ascitic fluid, consider fungal sepsis early)
-Managing portal hypertension
=Upper GI endoscopy
=Salt restriction/ diuretics for ascites
=Lactulose for encephalopathy

Question 28

Specific therapy for AH

Answer 28

-Corticosteroids for treatment of severe AH
=No response 40%
=Only 25-45% eligible
=Potential side effects (sepsis- STOPAH)
=25% decrease bilirubin in 1 week marker for steroid response
=Neutrophil to lymphocyte ratio may identify patients who will respond to corticosteroids

-Early liver transplantation as salvage therapy?
-Potential for growth factors, faecal microbiota transplantation, IL-1R blocker