liver Flashcards
component parts of the porta hepatis
- portal vein: blood from gut, pancreas, spleen
- hepatic artery: oxygenated from heart
- common hepatic duct: brings bile from liver to GB
what are kupffer cells?
= ‘stellate reticuloendothelial cells’ = modified macrophages
destroy old RBC and WBC
on the inner walls of sinusoids
describe the acinar lobule model of thinking about the liver
- loosely, an elliptical zone with central veins on either side and sinusoid in the middle
- Physiological context: different zones have different oxygenation and metabolic function
- Zone 1 is high in O2, high in toxins, high in nutrients - Closer to the portal triad
i- Zone 3 is low in O2, low in toxins, low in metabolites - Closer to the central vein
when do hepatocytes first start producing bile acids?
12 weeks gestation
how does the GB contract?
fat in duodenum > CCK > GB contracts + sphincter of oddi relaxes > bile released into D2
diff between conjugated and unconjugated bilirubin
- Conjugated = water soluble CANNOT CROSS BBB
- Unconjugated = fat soluble
describe bilirubin from synthesis to excretion
-heme >(heme oxygenase)>biliverdin
- biliverdin >(biliverdin reductase) >unconj bili
- unconj bili bound to albumin via hepatic bile duct to liver
- in hepatocyte: unconj > (UGT)> conj bili i.e. direct
- conj bili > excreted in bile > (gut bacteria) urobilinogen
- 80% in faeces: stercobilinogen > stercobilin
- 2% in urine: urobilinogen > urobilin
- 18% urobilinogen back to enterohepatic circulation
describe the conjugation of unconj bilirubin to conj bilirubin
unconj bilirubin + glucuronide (from UDP), by BUGT enzyme i.e. bilirubin uridine glucuronsyl transferase > bilirubin diglucuronide
AST vs ALT:
- which is more liver specific
- in CLD, which is usually greater?
- AST/ALT ratios: >2 when? <1 when? >20 when?
- ALT more liver, AST also in muscle, kidney, pancreas etc.
- CLD: ALT > AST, but may reverse as disease progresses
- AST / ALT >2 = alcoholic liver disease
- AST / ALT <1 = fatty liver disease
- AST / ALT >20 and isolated - extra-hepatic source
GGT vs ALP: which is more liver specific?
GGT from hepatocytes + bile ducts predominantly; ALP from liver + bone
how to tell if GGT elevated from obstruction vs induced?
GGT + ALP = obstruction
GGT only = induced
why does GGT rise in biliary obstruction?
GGT is an ectoenzyme > when obstruction occurs, bile acids destabilize membrane and GGT is leached out and enters the serum
transient hypophosphotaemia:
- what kind of ALP levels
- what age
- when
- resolves when
- Usually ALP >5x ULN
- Child <5 years
- Usually follows viral infection
- Resolves in 3 months
why are neonates predisposed to developing jaundice anyway?
- Increased production – shorter RBC survival (Fetal Hb) and higher RBC mass (high Hb)
- Decreased metabolism - Deficiency of UGT1A1, does not reach adult levels until 14 weeks of age
- Ethnic variation in conjugation (east asian, mutation in UGT1A1)
- Increased enterohepatic circulation – decreased gut motility, less conversion to stercobilinogen (sterile gut)
how does phototherapy work in jaundice?
- structural isomerisation to lumirubin - more soluble
- photooxidation to polar molecules - slow
- photo-isomerisation of 45,15Z to 45,15E isomer - less toxic, soluble. Also reversible cf lumirubin
breastfeeding jaundice vs breast milk jaundice
- when
- pathogenesis
breastfeeding
- starts D2-5
- insufficient feed
- peaks in 2 weeks, and progressively declines over 3-12 weeks
breastmilk jaundice
- later, D7-10
- breastmilk stuff e.g. metabolites of progesterone> inhibit UGT
causes of unconjugated hyperbili
increased production
1) haemolysis: Rh, ABO, G6PD def, PK def, sepsis
2) non-haemolytic: cephalohaematoma, polycythaemia
Decreased conjugation - Gilbert, C-N
Reduced excretion - breastfeeding jaundice
Other
- physiological jaundice, breastmilk, HYPOthyroid
causes of conjugated hyperbili / neonatal cholestasis
- infection (TORCH, sepsis)
- structural
- extra-hepatic: biliary atresia, choledochal cyst
- intra-hepatic: Alagille, PSC/PBC, PCKD
- functional: hepatitis - metabolic
- endocrine - hypothyroid
3 main causes of conjugated hyperbili
A1AT def
neonatal hepatitis
biliary atresia
what would these most likely represent if found on a liver biopsy?
ii. Bile duct paucity
iii. RAS positive diastase resistant granules
iv. MRD3 staining
ii. Bile duct paucity -> Alagille
iii. RAS positive diastase resistant granules -> A1AT def
iv. MRD3 staining -> PFIC3
consequences of chronic cholestasis
- growth failure
- ADEK vitamin def -> MBD, degen neuromusc syndrome (esp. vit E def)
- pruritus/xanthomas - can use urso
- portal HTN, ascites
- upper GI bleeding
- cirrhosis
causes of neonatal hepatitis (4)
1) idiopathic neonatal hepatitis (25%)
2) Aagenaes syndrome
3) zellweger syndrome
4) neonatal haemochromatosis
aaegenaes syndrome
- pathogenesis
- inheritance
- presentation
- cholestasis lymphoedema syndrome from lymphatic vessel hypoplasia
- AR
- episodic cholestasis; asymptomatic in between
zellweger syndrome
- what
- inheritance
- presentation
- prognosis
- peroxisome disorder > accumulation of VLCFA > cerebrohepatorenal syndrome
- AR
- severe, generalised hypotonia and markedly impaired neurologic function with psychomotor retardation
- fatal between 6-12 months
PFICs: compare type 1, 2,3, 4
PFIC1: ATPB81 gene, liver more susceptible to bile acids. low GGT
PFIC2: ABCB11 gene, reduced bile acid transport. low GGT. most common.
PFIC3: MDR3 gene, impaired phospholipid secretion, high GGT
PFIC4: TJIP gene, tight junctions leaky. normal/mild high GGT
Alagille syndrome: features
facies: triangular face, wide set eyes, broad nose bridge
butterfly vertebrae
JAG1
embryoxoton
pulmonary artery stenosis
tof
paucity of bile ducts and cholestasis
tx for pruritus 2nd to cholestasis
cholestyramine / rifampicin
biliary atresia: US findings
US: triangular cord sign = tubular echogenic cord of fibrous tissue, at bifurcation of portal vein
most close DDx of biliary atresia and how to distinguish
idiopathic neonatal hepatitis:
- INH FHx 20%
- BA may have other abnormalities e.g. asplenia/situs invertus
- BA won’t have pigmented stools, and won’t have bile stain duodenal suction
- BA more common to have weirdly palpable live
when does kasai have best outcome for biliary atresia?
if done <30 days of life
compare Crigler-Najjar Type 1 and Type 2, and Gilbert’s syndrome
C-N type 1 = complete lack of UDPGT (BUGT)
C-N type 2 = incomplete lack of UDPGT (BUGT)
Gilbert’s = TA insertion into the promoter region of UGT1A1 -> decreased activation
Crigler-Najjar type 1:
- inheritance + mutation
- Rx
- distinguishing from type 2
- AR + premature stop codon on UGT1A1 gene
- phototherapy daily
- cholestyramine + agar + CaCO3 all acts as binders so can use as adjuvants
- orlistat rarely used`
- phenobarbital is CYP450 inducer; type 1 will have no response
compare Dubin Johnson and Rotor syndrome
DBJ:
-MRP2 mutation»_space; canniculi transporter: impaired secretion of conjugated bili + other bile salt anions
-GB not visualised on cholecystogram
- total urinary corporphyrin normal, most corporphyrin I
- liver: black stained with melanin
Rotr:
- SLCO1B1»_space; code for bilirubin transporters for hepatocyte reuptake
- GB visualised
- total urinary corporphyrin high
- liver: normal
both don’t need treatment both mixed hyperbili.
Galactossaemia:
- genes involved
- GALT deficiency (classic)- converts galactose-1-phosphate to UDP-galactose
- GALK def - converts galactose to galactose-1-phosphate. cataracts only manifestation
- GALE def
galactossaemia: manifestations
eyes - cataracts
jaundice - mixed hyperbili
vomiting
FTT
cholestasis
RTA
ovarian failure
galactossaemia diagnosis - gold standard
nearly complete absence of galactose-1-phosphate uridyl transferase (GALT) activity in red blood cells (RBCs)
tyrosinaemia - mutation and manifestation
Deficiency of fumarylacetoacetate hydrolase -> FAA build up
‘hepatorenal’ tyrosinaemia - liver failure + fanconi’s RTA
Wilson’s disease:
- inheritance
- gene and pathogenesis
- age of onset
- AR
- ATP7B - encodes protein that transports copper in hepatocyte and binds it to apocaeruloplasmin»_space; lower circulating, bound Cu»_space; hepatotoxicity due to free radicals»_space; free Cu impacts other organs
- spectrum of disease: knockout of gene will be earlier
manifestations of Wilson’s disease
B-PEARL:
brain - Parkinsonian: tremor, dysarthria, rigidity, choreoform
psych - depression, personality change, psychosis
eye - K-F rings: Cu deposit in descemet’s membrane
anaemia - haemolytic, Coomb’s neg: RBCs can’t cope with Cu
renal - RTA + Fanconi’s
liver - hepatomegaly (+/- spleno), hepatitis, cirrhosis etc
Wilson’s disease: manifestations more common in younger vs older people with disease onset
younger: liver
older: neuro
Wilson’s disease: serum Cu, urinary Cu and caeruloplasmin levels
serum Cu: high
urinary Cu: high - can use 24h collection and assess response with chelator
caeruloplasmin: low (not bound, so apo- not turned into caeruloplasmin)
Wilson’s disease - management
1) low Cu diet e.g. low fish
2) chelators
- Oral D penicillamine
- Triethylene tetramine dihydrochloride (Trientine)
3) agents blocking intestinal absorption of cooper
- zinc: increases metallothionein protein in enterocytes > inc Cu uptake and trap it there
- Ammonium tetrhiomolybdate
potential side effects of penicillamine treatment
- 10-15% have worsened neuro condition
- hypersensitivity: goodpasture, SLE, polymyositis etc.
- low vit B6: penicillamine is an antimetabolite of vitamin B6 so need to supp with vit b6
A1AT def:
- inheritance
- gene affected + pathogenesis
- main clinical manifestations
- AR
- SERPINA1 gene: codes for A1AT protease inhibitor inc. elastase inhibitor.
- PiMM = normal. PiZZ = 10-20% A1AT = most comon for liver disease
- if no A1AT protein, no liver disease!
- COPD/emphysema: breakdown of alveolar elastin
- liver disease: abnormal protein trapped in hepatocytes
A1AT def: liver biopsy stains
periodic acid-Schiff positive, diastase resistant globules
neonatal haemochromatosis:
- pathogenesis
- maternal alloimmune injury
- Transplacental passage of specific reactive IgG > activates foetal complement cascade > production of MAC > foetal liver injury
- Iron deposition is a consequence rather than a cause of liver injury -> extrahepatic siderosis e.g. buccal glands with iron
liver abscesses: which part of liver more likely to be affected?
solitary liver abscess in R) lobe - 70%
Hep A / B / C
- incubation
HAV: 28d incubation, contagious 2wk-7days after jaundice
HBV: 1-5mo incubation
HCV: ~2mo incubation
different types of hepatitis A presentation
1) Prodromal stage (VIRAEMIA) = unwell with non-specific symptoms (nausea, anorexia)
2) Icteric stage/ classic hepatitis (IMMUNE RESPONSE) = 1-2 weeks later, jaundice
3) Hepatitis A relapse after initial improvement
4) Cholestatic hepatitis = initial symptoms as in classic hepatitis A, prolonged pruritis
5) Fulminant hepatitis (1-5%) = initial presentation as in classic hepatitis A»_space; rapid deterioration with confusion and decreased LOC
most common hepatitis virus in the world
Hepatitis A
AST/ALT in relation to hepatitis A symptoms
AST/ALT rise occurs BEFORE jaundice
How is HBV transmitted
1) Vertical
2) Horizontal – children in endemic country
3) Blood-borne
4) Sexual
phases of HBV infection
1) immune tolerant phase months-decades long: high HBV load, normal AST/ALT
2) immune clearance: high AST/ALT as body tries to clear
3) immune control = inactive carrier: seroconversion HBeAg –ve to anti-HBe positive. LFTs normal.
4) immune escape: LFTs rise again
neonates with HBV: how many become carriers
95% become asymptomatic chronic HBV carriers
HBV serology: what does each marker mean
HBsAg
HBsAb
HBcAb
HBeAg
HBeAb
HBV DNA
HBsAg = active infection, first to appear
HBsAb = immunity, either vaccination or infection
HBcAb = Infection with HBV – either past or current
HBeAg = active viral infection – either acute or chronic
HBeAb = indicates Seroconversion; goal of treatment
HBV DNA = Amount of replication
treatment options for HBV to reduce viral load
- Pegylated interferon
- Weekly S/C injection for 48 weeks
- AE = fever, myalgia, lethargy, depression, anaemia, thrombocytopenia, neutropenia
- 35-40% seroconvert OR drop viral load, 8% lose surface antigen at 3 years - Antivirals = entecavir + tenofovir
- Oral tablets 1/daily
- Well tolerated, taken long term but cannot be given with pregnancy
- 90% drop viral load to undetectable at 12 mo, E seroconversion at 15%/year, <1% loss of surface Ag
complications of HBV infection
- fulminant hepatitis
- cirrhosis
- HCC
- HBV associated GN
HCV transmission
blood borne; sexual unlikely
acute HCV infection - symptoms?
very vague, fatigue/nausea - so most don’t get picked up
HBV vs HCV cure rate
HBV is lifelong, can’t be cured
HCV can be cured
treatments for HCV infection (2), and what determines response to therapy?
PEG IFN and ribavirin
1. Genotype of virus
- IL28B genotype of the patient indicates likelihood of response to therapy
complications of HCV infection
1) Cirrhosis
2) Rheum: myalgia, fatigue, arthralgias, and arthritis; Sjogren’s
3) porphyria cutanea tarda and lichen planus
4) Cryoglobulinaemia = single or mixed immunoglobulins that undergo reversible precipitation at low temperatures
5) MPGN
6) Eye complications = keratoconjunctivitis sicca (dry eyes), which may be a manifestation of Sjogren’s syndrome and Mooren ulcer (a rapidly progressive, painful ulceration of the cornea)
HDV:
- relationship to HBV
- treatment
- prevention
- need HBV for envelope
- chronic HDV - IFN alpha
- HBV vacc prevents HDV
definition of acute hepatic failure
- Acute liver related illness (jaundice, elevated transaminases) with no history of known chronic disease (<8 weeks), PLUS
- Coagulopathy – not corrected by vitamin K
a. INR >1.5 or PT >15s with encephalopathy
b. INR >2.0 or PT >20s with or without encephalopathy
definition of portal HTN
elevation of portal pressure >10-12 mmHg
clinical manifestations of CLD
hands: leukonychia, palmar erythema, pale palmar creases, asterixis
skin: bruising, pruritus, muscle wasting, jaundice, xanthomas, spider naevi, gynaecomastia, caput medusae
hepatomegaly
portal HTN -> ascites, varices, bleeding
encephalopathy
hepatorenal syndrome
hepatopulmonary syndrome
hepatorenal syndrome
- splanchnic vasodilation, mesenteric angiogenesis, and decreased effective blood volume with resulting decreased renal perfusion
- Hallmark is intense renal vasoconstriction with coexistant systemic vasodilation
- Diagnosis supported by oliguria, urine electrolyte abnormalities (urine sodium <10meq/L, fractional excretion <1%, normal sediment), absence of hypovolaemia and exclusion of other causes
hepatopulmonary syndrome
1) hypoxaemia 2) intrapulmonary vascular dilatation 3) liver disease
- Intrapulmonic R to L shunting of blood resulting from enlarged pulmonary vessels that prevents RBC traveling through the center of the vessel allowing adequate exposure to oxygen-rich alveoli
- Shunting of vasodilatory mediators from the mesentery away from the liver is thought to contribute
