Hepatology Flashcards
Alcoholic liver disease - genetics
PNPLA3
= patatin-like phospholipase domain-containing protein 3
= adiponutrin (ADPN)
= acylglycerol O-acyltransferase or calcium-independent phospholipase A2-epsilon (iPLA2-epsilon)
Human enzyme that is encoded by PNPLA3 gene
Chromosome 12
MORE PRONE TO DEVELOPING FIBROSIS
NAFLD - biochemistry
ALT > AST
ALT < 2-3x ULN
Alcoholic liver disease - biochemistry
AST 2-6x ULN
Alcoholic liver disease - histology
Mallory’s hyaline
Acute alcoholic hepatitis: neutrophils, necrosis of hepatocytes, collagen deposition, fatty change
Maddrey’s Discriminant Factor
4.6 x (PT patient - PT ref) + total bilirubin
- for alcoholic hepatitis
- only for short-term prognosis
- utilises PT, bilirubin
> 32 = poor prognosis and should be given steroids
MELD
= Model for End-Stage Liver Disease
Use:
- 3 month survival aged 12+
- primarily used to stratify patients on liver transplant waiting lists
- predicts mortality after transjugular intrahepatic portosystemic shunt (TIPS), cirrhotic patients undergoing non-transplantation surgical procedures, acute alcoholic hepatitis, acute variceal haemorrhage
- utilises creatinine, bilirubin, INR, Na
- scores from 6 –> 40
- score => 32: short-term mortality 50%
- any cirrhosis etiology
Alpha-1 anti-trypsin deficiency
Lack of protease inhibitor normally produces by liver
A1AT role: to protect cells from enzymes e.g. neutrophil elastase
Chr 14
Autosomal recessive/co-dominant inheritance
Alleles classified by electropheritc mobility
M = normal
S = slow
Z = very slow
Normal = PiMM
Homozygous PiSS = 50% normal A1AT levels
Homozygous PiZZ = 50% normal A1AT levels
Manifest disease - usually PiZZ
Pentoxifylline
Xanthine derivative
- competitive nonselective phosphodiesterase inhibitor
- inc intracellular cAMP, activates PKA, inhibits TNF and leukotriene synthesis, reduces inflammation and innate immunity
Used in alcoholic liver disease if steroids contraindicated or if early renal failure
Improves in-hospital survival
Wilson’s disease
Copper overload
Autosomal recessive
ATP7B gene
Chr 13
Encodes ATP7B protein = Wilson disease protein (WND)
Copper transporting protein
Clinical:
- hepatic (first sign in children), DECREASED ALP as Cu interferes with synthesis
- psych
- neuro (first sign in adolescents)
- ophthal: Kayser-Fleischer rings (deposition in Descemet’s membrane)
- renal: RTA
- heamolysis
- blue nails
Inv:
- DECREASED CAERULOPLASMIN, dec total serium copper
- inc 23 hr urinary, hepatic and free serum copper
- liver Bx to confirm
Mx:
- chelating agent (penicillamine, trientine hydrochloride, tetrathiomolybdate)
- low copper diet
- liver Tx for acute liver failure
Hereditary haemochromatosis - genetics
Autosomal recessive
- most common AR disorder in caucasians
Mutations in HFE gene responsible for majority
HLA-A3 locus, chr 6
x2 missense mutations
C282Y
- 85% of patients with pheotypic HH
- disrupts HFE-B2M-TFR1 complex
H63D
- allele frequency 63%
- homoxygote/heterzygote/compound heterozygote
Hereditary haemochromatosis - clinical
Chronic liver disease
- most common organ affected
- hepatomegaly, abnormal LFTs, fibrosis, cirrhosis
Athralgia/arthritis
- 2nd and 3rd MCP
Endocrine
- T1DM
- hypogonadism
Cardiac
- cardiomyopathy
- CCF
- arrhythmias
Classic triad: bronze skin, diabetes, cirrhosis - RARE
Hereditary haemochromatosis - investigations
Fasting morning transferrin saturation
- most sensitive initial screening tool
- NOT Sp
Serum ferritin
- rises later
- note: is an acute phase reactant
- > 1000 indicator for need for Bx
HFE mutation
- indicated in Fe overload phenotype, FHx of HFE-related HH
Second line genetic testing of young adults without significant HFE gene mutations
- hemojuvelin (HJV)
- hepcidin (HAMP)
- transferrin-2 receptor (TRF-2) fene mutation
Liver biopsy
- if ferritin > 1000
- Prussian blue stain
MRI liver and heart +/- ECHO
Hereditary haemochromatosis - treatment
Venesection
- drop ferritin by 50 initially then maintain <100
- iron chelating agents
King’s College Criteria
- for paracetamol induced hepatic failure
Arterial pH < 7.3 (24 hours post ingestion)
Or
All 3 of:
- INR > 6.5
Creat > 300
- encephalopathy grade III or IV
King’s College Criteria
- for non-paracetamol induced hepatic failure
INR > 6.5;
Or
3 of 5 of:
- aged <11 or >40
- bili > 300
- time of jaundice onset to come > 7 days
- INR > 3.5
- drug toxicity, regardless of whether it was the cause of the acute liver failure
