NAFLD and Alcoholic Liver Disease Flashcards
Epidemiology of NAFLD
-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
Describe NAFLD as a spectrum of disease
-Healthy
-Isolated steatosis (NAFL)
-Steatohepatitis (NASH)- activity and scarring (steatosis and ballooning for activity)
-Fibrosis/ cirrhosis
-Hepatocellular carcinoma
4 stages of fibrosis
- Periportal or perisinusoidal
- Periportal AND perisinusoidal
- Bridging fibrosis (bands between vascular structures)
- Cirrhosis (thick bands form nodules)
Why is degree of liver fibrosis important?
-Main predictor for clinical outcomes in fatty liver disease
Pathogenesis of NASH
-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
What is included in full liver screen?
-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
Clinical features of NAFLD
-Fatigue
-Mild RUQ pain
-Metabolic syndrome (T2DM, dyslipidaemia, high BP)
-Unexplained liver enzyme abnormalities
-Incidental finding of fatty liver on imaging
Findings from clinical examination in NAFLD
-Central obesity
=May have normal BMI (10% ‘lean’ NAFLD)
-High BP, xanthelasma, hepatomegaly, cirrhosis?
Routine blood tests in NAFLD
-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
Diagnostic goals of NAFLD
- Exclude other aetiologies (may coexist with NAFLD)
- Identify risk factors for NASH
- Assess and quantify fibrosis
=Serum and imaging biomarkers
=Role of liver biopsy? - Identify and treat co-morbidities
=Obesity, diabetes, hypertension, cholesterol
What diseases need to be excluded in NAFLD patient?
-Alcoholism= common, father with alcoholism
-Autoimmune liver disease= mother with hypothyroidism
-Wilsons disease= devasting if not treated
-Viral hepatitis, haemochromatosis
Examples of other causes of fatty liver
-Excessive alcohol consumption
-Malnutrition
-Medications (amiodarone, valproate, tamoxifen, methotrexate, HAART)
-Parenteral nutrition
Examples of other liver diseases that can present with steatosis
-Chronic hepatitis C (genotype 3)
-Wilson’s disease
-Metabolic abnormalities (lipodystrophy, lysosomal acid lipase deficiency)
Clinical predictors of NASH in patients with NAFLD
-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
Examples of simple serum-based fibrosis tests
-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)
Compelx tests for fibrosis
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)
Treatment for NAFLD
-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
Pharmacological targets for NAFLD medications
-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
Co-morbidities in NAFLD
-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
Spectrum of alcohol related liver disease
-Normal
-Acute alcoholic hepatitis (severe exposure, 10-35%)
-Steatosis (90-100%= fatty change and perivenular fibrosis)
-Cirrhosis (8-20%)
Describe acute alcoholic hepatitis
-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)
Clinical history in AH
-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)
Physical signs of AH
-Fever (25%)
-Hepatomegaly (tender) (75%)
-Jaundice (60%)
-Ascites (30-60%)
-Hepatic bruit (rare)
Classical laboratory findings in AH
-Cholestasis (bilirubin >80)
-Leucocytosis (neutrophilia)
-AST: ALT >2
-Moderate raised AST (<300)
