Hepatic Dz

Question 1

Important cells in hepatic fibrosis (7)

Answer 1

Stellate - undergo transdifferentiation to produce type I and III collagen which is the cause of fibrosis

Portal Fibroblasts - produce some ECM, induce vascular remodelling and stimulate endothelial cell to make ET1

Cholangiocytes - activate portal fibroblasts by producing chemoattractants

Sinusoidal endothelial cells - activate HSC via ET1, PDGF, TGFB, NO

BM derived mesenchymal cells - differentiate to type I collagen producing myofibroblasts

Macrophages - activate HSC by ROS, PDGF, TGF-B
- resolution phenotype can remove fibrosis

NK cells - fibrosis resolution

Question 2

Main profibrotic mediators in liver (4)

Answer 2

PDGF -most potent factor that induces proliferation of HSCs. Released by platelets, sinusoidal endothelial cells, activated liver resident macrophages, and myofibroblasts during ongoing disease

TGF-B - upregulation of collagen types I and III, and TIMP-1, and downregulation of MMPs → The result is increased capability of HSCs to produce ECM components and inhibition of ECM removal
(Produced by hepatocytes, macrophages, sinusoidal epithelial cells, platelets and activated HSCs)

Endothelin 1 - vasoactive peptide that promotes proliferation, contraction, and the maintenance of the activated state of HSCs. cause stellate cell contraction and reduce sinusoidal space thus increasing resistance
(sinusoidal endothelial cells stimulated by portal fibroblasts)

ROS - deplete antioxidant systems of liver and intensify inflammation.
Produced by macrophages and other inflammatory cells

Question 3

Common causes of hepatic fibrosis in dogs

Answer 3

chronic hepatitis; Cu assoc hepatitis; lobular dissecting hepatitis; EHBDO; RSCHF; caval obstruction; ductal plate malformations

Question 4

How is hepatic fibrosis reversed

Answer 4

Monocyte-derived macrophages with a pro-resolution phenotype seem to be important in the reversal of fibrosis, because they produce MMPs, which degrade the ECM or mediate apoptosis of myofibroblasts

Main mechanism for the resolution of fibrosis seems to be the apoptosis or senescence of activated myofibroblasts (HSCs), which removes the source of TIMP-1, resulting in increased matrix metalloproteinase activity

Question 5

Possible Role of RAAS in hepatic fibrosis

Answer 5

angiotensin II binds to angiotensin II receptor type I, activating profibrotic mechanisms including induction of TGF-Beta

Cleavage of AngII –> small protein angiotensin (1-7) form and binding to their receptors activates a counter regulatory pathway
(ACEi or Ang receptor blockers inhibit profibrotic RAS and can attenuate fibrosis in animal models.)

Question 6

Findings of cytology and histo in Hepatic fibrosis and potential non-invasive markers (5)

Answer 6

Cytology: increased mast cells and spindle cells reported to have reasonable accuracy.
Histopathology: often heterogeneous distribution, need 3-12 portal triads for accurate diagnosis (11 recommended by pathologists)
Masson’s trichrome stains collagen I; Reticulin stains type III
Increased amounts of fibrillary collagens (types I, III, and V), nonfibrillary collagens (types IV and VI), and glycosaminoglycans and proteoglycans (eg, fibronectin, tenascin and laminin, perlecan, decorin,aggrecan, and fibromodulin)

Gene Expression: upregulation of gene expression (PDGF, TGFB, TIMPs). Alterations in expression from FNA samples showed significant correlation with severity of fibrosis.

Serum Hyaluronic acid: increased in dogs with hepatic disease in particular cirrhosis. Conflicting results in canine studies, but considerable overlap.

miRNA - 200 and 126 may correlate with severity. 122 correlated with stage of fibrosis in CH patients

JVIm 2018 - evaluation of biomarkers for severity of fibrosis. None of IL-6, CCL2, CRP, AST:ALT ratio were useful in single measurements. IL6 was higher in severe fibrosis (may be useful for trends)

Elastography - non-invasive test of liver stiffness using ultrasound shear waves. Needs further evaluation

Question 7

Treatment of Hep Fibrosis

Answer 7

Address underlying cause of inflammation - chelation in Cu-associated hepatitis, treat infectious causes. Immunomodulatory therapy has variable response in dogs with CH

Antioxidant treatment: cytoprotective effect by scavenging ROS or increasing tissue concentrations of antioxidant enzymes or proteins such as superoxide dismutase, catalase, glutathione peroxidase, glutathione, or metallothionein.
no direct evidence that antioxidants decrease hepatic fibrosis or improve clinical outcome for most hepatobiliary diseases in dogs, there is a rationale for using them.
Silymarin also may inhibit hepatic fibrosis by decreasing HSC DNA synthesis. in other species that ursodeoxycholic acid also may have antiapoptotic properties

Colchicine - a microtubule assembly inhibitor shown to decrease hepatic fibrosis in rodent models.

RAS Blockade - Targeting the RAS with ACE inhibitors, angiotensin receptor blockers, and angiotensin (1-7) receptor agonists has been shown to attenuate liver fibrosis in rodent models. Involvement of the RAS in hepatic fibrosis has not yet been demonstrated in dogs and so clinical trials assessing efficacy of these drugs for this purpose are premature

Question 8

How does ascites develop in portal hypertension
And type of effusion based on location of cause

Answer 8

Ascites: increased hydrostatic pressure and release of splanchnic vasodilatory substances (NO) due to hypertension → fluid enters interstitium → decreased ECV → SNS compensatory increase in CO and RAAS → ADH release and volume expansion → worsening hypertension
+/- contribution of low oncotic pressure from hypoalbuminemia

Modified Transudate: seen in post-sinusoidal or post-hepatic disease
Pure transudate: seen in prehepatic or sinusoidal obstructive disease.

Question 9

Different locations of causes of portal hypertension and the DDX

Answer 9

Prehepatic: Increased resistance in portal vein before it reaches liver
congenital, intraluminal obstruction, extraluminal obstruction

Intrahepatic: increased resistance in portal vein tributaries, sinusoids or small hepatic veins. Can be non-cirrhotic which occurs with congenital disease, or cirrhotic seen with chronic acquired parenchymal disease due to contraction of connective tissues (produced by HSCs) causing obstruction of intraparenchymal vessels
→ if severe reversion of portal flow backwards into portal veins (hepatofugal flow) if there are mAPSS
Presinusoidal (PHPV, cholangitis, ductal plate malformations, arteriovenous fistula)
Sinusoidal (cirrhosis, chronic hepatitis/cholangiohepatitis, ductal plate malformations, lobular dissecting hepatitis)
Postsinusoidal (veno-occlusive disease)

Posthepatic: Increased resistance in hepatic vein or CVC (= Budd-chiari syndrome). RSCHF, hepatic vein obstruction (intra/extra-luminal)
May see jugular venous distension or have heart murmur.
Does not cause mAPSS

Question 10

What is normal portal venous pressure - how is portal hypertension caused

Answer 10

Normal portal pressure is 8-10mmHg
Primary causes- increased flow of blood or increased resistance to flow (obstruction or dynamic due to imbalance of vasodilatory/vasoconstrictive substances)

Increased Endothelin 1, AngII, LTs - vasoconstriction
Reduced NO, PGE2, CO2 (vasodilatory) and reduced responsiveness
Stellate cell VEGF and PDGF → smooth muscle proliferation → capillarisation of sinusoids
Hypertension → splanchnic vasodilation through NO and LPS (inducing NOS) → higher portal blood flow and worsening of hypertension

Question 11

Treatment targets in portal hypertension (Tx of sequelae and addressing vascular changes)

Answer 11

Sequelae
Management of: Fluid overload; Increased abdominal pressure; Na excess
Ascites: dietary Na restriction, add spironolactone if no improvement. Paracentesis if causing respiratory difficulty.
Gastropathy: PPi and mucosal protection. ACVIM said low LoE as a prophylactic but likely useful in cases where ulceration is present.
- Management of HE

Splanchnic Vasoconstriction: B blockers (atenolol, carvedilol) used in humans to lower PVP but experimental and clinical study in dogs found no benefit
Somatostatin - inhibits splanchnic vasodilator release. Use in portal hypertension not reported (used in other disease)
Vasopressin - potent splanchnic vasoconstrictor but also affects systemic BP and causes arrhythmia/myocardial effects.

Sinusoidal vasodilation: to reduce intrahepatic vascular resistance. May be accomplished by NO analogues or statins which increase NO production in the liver.
No data in vet med
RAAS blockade: ARB (losartan - AngII R block) used in humans to decrease PVP without causing systemic hypotension. May also alter splanchnic endothelial dysfunction and inhibit stellate cell transdifferentiation. JVIM hepatic fibrosis review said not enough evidence the same pathways are upregulated in dogs with fibrosis/portal HT yet to consider their usage.

Question 12

Causes of gastropathy in liver disease

Answer 12

Thought to be caused by reduced gastric blood flow impairing normal defences

mucosal oedema

reduced gastrin removal, possibly microthrombosis

Altered motility, SIBO due to altered biome from reduced bile salts.

Question 13

Evidence for immune mediated canine chronic hepatitis

Answer 13

Moderate to strong in ACVIM consensus
presence of LP infiltration,
documented abnormal expression of MHC II (Doberman);
positivity for autoantibodies;
familial histories of CH;
female predisposition;
positive response to immunosuppression

A presumptive diagnosis based on elimination of all other aetiologies as well as a documented improvement with immune suppression.

Question 14

Infections with association with chronic hepatitis and LoE

Answer 14

A presumptive diagnosis based on elimination of all other aetiologies as well as a documented improvement with immune suppression.

Question 15

WSAVA Definition of Chronic hepatitis on histo

Answer 15

moderate to marked mixed inflammation infiltrate with hepatocyte necrosis/apoptosis
+/- ductular proliferation, fibrosis, regenerative nodules

Question 16

Diagnostic challenges for Cu hepatitis(5) - ACVIM 2019

Answer 16

• Lobe to lobe variation
• Regenerative nodules have reduced Cu levels
• Fibrosis impairs quantification
• later stage liver disease impairs ability to determine distribution of Cu accumulation in lobule
• ‘Grey zone’ Cu levels of 600-1000 ug/g. Don’t know exactly at what point Cu levels are toxic to hepatocytes and likely individual threshold is varied by env/genetic and dietary factors.

Question 17

Pathogenesis of Cu hepatitis in dogs and ACVIM theory

Answer 17

Abnormal hepatocyte Cu excretion, excessive dietary intake or both. Chronic cholestasis can also predispose to Cu accumulation
The level of Cu in hepatocytes required to cause CH is not known

Bedlington Terrier - COMMD1 mutation, impairs Cu excretion by hepatocytes thus causing excess accumulation in cells. Autosomal recessive mutation. Genetic screening and selective breeding has greatly reduced incidence.
Labrador: mutations in Cu transporters in liver and GIT have been identified (altered excretion and increased uptake) but predictive utility of genetic screening tests has not been established
OTher:, Dalmatian, Doberman, WHWT. Any breed can get Cu CH.

ACVIM consensus proposes a correlation with change to more bioavailable Cu and absence of maximum guidelines in AAFCO or NRC recommendations (so often minimums can be exceeded 2-3x)

Question 18

Histo findings for Dx of Cu hepatitis

Answer 18

evidence of CH associated with hepatic copper accumulation (usually centrilobular)
Cu staining demonstrating centrilobular hepatocyte Cu accumulation
Hepatic Cu quantification >1000ug/g dry weight

Question 19

Findings in reactive heptopathy histo

Answer 19

mild to moderate mixed inflammation in portal region.
NO fibrosis, apoptosis/necrosis/architectural change.

Question 20

Metabolic causes of chronic hepatitis in dogs

Answer 20

a1-antitrypsin deficiency can cause retention of abnormally folded proteins in hepatocytes → Cocker Sp, rare genetic disorder
Abnormal porphyrin metabolism → GSD colony, accumulation of porphyrins in hepatocytes.

Question 21

Best screening test for chronic hepatitis in dogs

Answer 21

Persistent (>2 months) unexplained increases in serum ALT activity with or without other laboratory changes is the best screening test currently available for early detection CH

Question 22

Recommended screening prior to liver bx for coagulation

Answer 22

Fibrinogen <100
PCV <30%;
plt <50,000;
PT/APTT >1.5x normal;
vWF <50%; BMBT >5 mins

Question 23

Tx recommendaitons for Cu chronic hepatitis

Answer 23

Chelation - D-penicillamine

Diet restriction - dont need protein restriction unless HE

Long term diet restrction +/- Zn

+/- immunomodulation if concurrent LP inflam.

Don’t use Zn with D-Pen.

Question 24

ACVIM recommendations for immunosuppression idiopathy/immune mediated Chronic hepatitis
and any recent publications (1)

Answer 24

Immunomodulation: Collectively the studies published support the existence of CH dogs responsive to immune suppression. Mostly small retrospective study evidence, variable breeds and often concurrent therapies/different dosing strategies. Not all evaluated Cu. Biopsy follow up rarely performed
ACVIM Panel observation experience / lack of consensus:
- All reported pred efficacy as first line, but AEs complicate use and monitoring (problematic in advanced liver dz)
- Most combine with 2nd drug with goal to use that solely long term. Some use single agent cyclosporine to avoid pred AEs.
- Mycophenolate, Azathioprine, Cyclosporine all anecdotally used.

Also give hepatoprotectants, restrict Cu if levels elevated. Manage complications.

JVIM 2019 - 48 dogs presumed idiopathic CH Tx with cyclosporine and hepatoprotectant. Biochemical remission (ie no histo) in 79%.
Hepatoprotectant use not assoc with remission, neither were clinical severity scores, ascites, duration or dose. Retrospective, low LoE

Question 25

MOA of D-penicillamine and AEs

Answer 25

Monothiol chelating agent that binds copper, lead, iron, mercury and forms stable complexes that are renally excreted.
Also has antifibrotic effects - inhibits enzyme necessary for collagen synthesis and collagen cross-linking.
Also anti-inflammatory

Takes months to years for hepatic copper levels to ↓ but clinical signs improve over a few weeks. Potentially due to sequestration in non-toxic form.

Adverse GIT effects common - anorexia, nausea, vomiting
Some panel members preferred coadministration of a short course of low-dose corticosteroids to stimulate appetite when dogs are inappetent
Less common are hypersensitivity reactions and ICGN with proteinuria

Question 26

sAME and silybin MOAs

Answer 26

Nutraceutical that plays a central role in synthesis of glutathione via the transsulfuration pathway.
May help to prevent oxidative damage by preventing depletion of hepatic glutathione.
- Anti-inflammatory properties, ↓ production of pro-inflammatory cytokines (aminopropylation)
- Stabilise cell membranes (transmethylation).
- Modulate apoptosis

Silybin - - Scavenging free radicals
- ↓ lipid peroxidation
- Anti-inflammatory effects
- Inhibition of hepatic fibrosis

Question 27

UDCA MOA (4)

Answer 27

• ↓ intestinal absorption and hepatic synthesis of cholesterol → ↓ cholesterol saturation of bile
• Protects liver from damaging effects of hydrophobic bile acids retained in cholestasis (cytoprotective)

-↑ bile flow through replacement of hydrophobic bile acids and secretion with HCO3 which causes osmotic draw (choleretic effect)

• Immunomodulation: ↓ IGg production and ↓ IL 1 and 2.

Question 28

Diet recommendations in chronic liver disease

Answer 28

energy requirements are increased from normal due to the catabolic nature of the liver. Patients usually require an energy dense diet to minimize the volume of food required to reach RER

Cu restriction - if indicated based on biopsy, and combine with chelation if severe

Protein restriction only if HE - otherwise ensure high qual, easily digestible. Plant based and dairy protein have been shown to prolong the time to development of HE
Cats need taurine and arginine in adequate amounts

high requirement for dietary soluble carbohydrates to have more glucose available for synthesis of fatty acids and energy generation

increase soluble fibre – fermentable can alter bacterial flora, reduce enteric ammonia production

Question 29

Different types of liver toxicities and different casues

Answer 29

Toxins may be cytotoxic causing hepatocyte necrosis through direct injury, or they may be cholestatic where they inhibit/downregulate the canalicular transporters → interrupt bile salt efflux or damage mitochondria.,

Dosage dependent (inhibit transporter pumps, generate reactive metabolites causing oxidative stress, interference with mitochondrial function or cellular respiration or induce cytP450 causing bioactivation of environmental toxins): phenobarbitone, paracetamol, azole antifungals, CCNU, azathioprine, amiodarone, tetracyclines

Idiosyncratic (atypical metabolites causing oxidative stress; binding protein and forming hapten, mitochondrial damage): TMS, Carprofen, Diazepam

Environmental: aflatoxin, Cyad, Xylitol, Amanita mushroom, Blue-green algae

Question 30

Hepatocyte zones and what they are susceptible to

Answer 30

Zone 1 hepatocytes: most susceptible to direct toxicants as highest dose exposure
Zone 3: most susceptible to hypoxic injury and contain cytP450 which can generate toxic metabolites from xenobiotics

Question 31

2 recent AVJ articles on liver toxicities

Answer 31

AVJ 2022 - Indospicine toxicity (arginine analogue that accumulates in tissues of animals eating Indigofera plants) from pet meat produced by a knackery.

AVJ 2020 - 130 cases of Cycad palm toxicosis, 1.5% died, 10% euth. Lower ALT assoc with survival. Activated charcoal treatment reduced risk of death by 82%.

Question 32

Differentials for feline liver dz

Answer 32

2 most common feline hepatopathies are: cholangiohepatitis (acute suppurative or chronic), and lymphocytic portal hepatitis/ CCH
Cholangitis/cholangiohepatitis was the most common primary histopathologic diagnosis made in 27 to 39% of feline liver biopsy submission

Cholangitis = neutrophilic, lymphocytic, destructive and chronic (associated with liver fluke infestation).

lipidosis, amyloidosis and feline infectious peritonitis, ductal plate malformations

Question 33

Evidence for immune mediated cause of Feline Nonsuppurative/Lymphocytic liver dz

Answer 33

1) CD3+ lymphocyte infiltration around ductules and periportal region
2) portal distribution of CD79+ B lymphocyte aggregates
3) regional MHC II expression
4) Targeted biliary destruction
5) clinical and histological improvement with immune suppression

JFMS 2017 and JSAP 2022 reviews

Question 34

Possible triggers for feline NS-CCHS

Answer 34

Activation of cholangiocytes by ischaemia, infection, cholestasis, toxins
Activated cholangiocytes have a proliferative, pro-fibrotic and pro-inflammatory response. With chronic activation they contribute to biliary fibrosis → ductopenia

• IBD present in 60% of cats in one study (a known risk factor in humans with primary sclerosing cholangitis)
• Pancreatitis with IBD present in 20% of LC cases (of 25)
• Bacterial: low LoE, isolated from bile in <20% of cases. No evidence to suggest a direct infectious link as rarely identified at time of diagnosis (but does not mean they are not a trigger)

Question 35

What is feline lymphocytic portal hepatitis

Answer 35

subtype of LC/NS-CCHS that has less effect on biliary ductules but rather LP inflammation in portal triads. More often detected in older cats, may be associated with ageing

could reflect various chronicity of different aetiology/pathogenesis of disease

Question 36

Feature that helps to differentiate small cell lymphoma from LC cholangitis

Answer 36

both can have monoclonal/polyclonal T cell expansion.Presence of bile duct targeting or ductopenia seems to be associated with LC rather than lymphoma

IHC and PARR - may provide utility in differentiation from lymphoma, though preliminary data did not support their utility

Question 37

Recommended Tx of NS- CCHS

Answer 37

Small, uncontrolled retrospective information only.
Pred: study comparing to Tx with UDCA alone demonstrated better long-term survival in pred group but unclear if UDCA confers benefit as adjunct so still recommended. Immunosuppressive doses that are tapered ideally based on biochemical enzymology and repeat biopsy (though latter is rarely performed)
Persistent or progressive ALT/ALP elevations suggest ineffective treatment or incorrect dx.
Chlorambucil - may be used as 2nd line agent

ABX: a 2 week course recommended in cats without positive culture, due to possibility of secondary infection and potential to worsen this with immune suppression.

Colchicine - could help with fibrosis, not really trialled
Non:Specific:
Antinausea, analgesia, Nutrition (consider hypoallergenic or highly digestible if concurrent IBD or pancreatitis)
Appetite stimulation as necessary (may need prolonged dosing interval in reduced liver function)
Vit K, E, D, B12, Taurine replacement
Hepatoprotectants: UDCA, sAMe

Ascites and HE are uncommon or very end stage

Question 38

Neutrophilic cholangitis proposed pathogenesis

Answer 38

There is compelling evidence for bact having a primary role in the pathogenesis of NC in cats just as they do in humans, with bacterial isolation reported as 20-60% and more recently 94% when using multiple bacterial IHC markers and FISH. However, there may be a small subfraction of NC that is primarily immune mediated.

1) Mechanical or functional biliary obstruction - changes microenv, enhances bacterial colonisation
2) bacterial infiltration

Source of Bacteria: ascension from duodenum or translocation from SI and haematogenous delivery in portal blood.
- Portal venous route may be more likely in the >50% of cats that have concurrent IBD or pancreatitis (further 20%) increasing risk of translocation (through dysbiosis, altered barrier function)

Question 39

Histological findings in neutrophilic and lymphocytic cholangitis

Answer 39

Neut: neutrophilic infiltrate in bile ductule lumens, associated with bile duct or biliary epithelial cells. May extend into the hepatic parenchyma causing periportal hepatocyte apoptosis or necrosis (cholangiohepatitis)
ACUTE - oedema, minimal duct hyperplasia and no fibrosis
CHRONIC - mixed neuts and monocytic inflammation, bile duct hyperplasia, fibroplasia or fibrosis

Lymph: infiltration of lymphocytes in portal region with varying bile duct proliferation and fibrosis.
Often there are dense aggregates of small lymphocytes in the portal region with occasional plasma cells. Lymphocytes may also infiltrate the biliary epithelium suggesting bile duct targeting and causing progressive ductopenia.
Wide range of histological features that could reflect various chronicity of different aetiology/pathogenesis of disease (portal hepatitis vs cholangitis and ductopenia)

Question 40

Comorbidities reported in JAVMA 2022 Centre study of 168 cats, and outcome.

Also significnace of choleliths reported in JVIM 2023 study

Answer 40

JAVMA 2022 Center Clinical presentations in 168 cats - hyporexia, hyperbilirubinemia, lethargy, vomiting and jaundice are most common.
Comorbidities: 50% EHBDO, 42% choleliths, 40% cholecystitis, 44% ductal plate malformations.
U/s detected only 58% of choleliths
cholecystectomy associated with survival advantage if choleliths

72% survive to discharge, MST of 29.3 months.
Poorer prognosis if EHBDO and need for corrective surgery. 30-40% die within 1 week.

JVIM 2023 - significance of choleliths in 98 cats, incidental in 41%, symptomatic in 59% (concurrent hepatobiliary disease present in 83% of these). No evidence of clinical signs developing in the cases with incidental choleliths.
Of symptomatic cases 74% survived to d/c and EHBDO was associated with poor prognosis

Question 41

When to consider pred in neutrophilic liver disease in cats

and justification

Answer 41

Failure to improve within 2 weeks of appropriate ABx and other supportive care (or deterioration prior to this) should prompt consideration of other possible disease:
- Additional steroid therapy for immune mediated aetiology at anti-inflammatory doses then gradually weaned. Optimal duration varies on a case by case basis.
- Reason for benefit of steroids: concurrent pancreatitis or IBD, immune mediated mechanism, improvement of bile flow and reduced tissue oedema from inflammation

Question 42

3 proposed mechanisms of Triaditis pathogenesis and any evidence for each

Answer 42

1) Pancreatitis as inciting cause: direct extension of inflammation to adjacent SI and shared duct; promotion of dysbiosis (increases translocation of bacteria); potential to cause EHBDO and promote bacterial colonisation.
Supported by isolation of bacteria from bile/liver and positive FISH in pancreas. Vomiting can also cause reflux of duodenal chyme into shared duct. Bacterial infection may be the result of ascending bact from duct or haematogenous from increased translocation.

2) SI Inflammation and dysbiosis: inflammation causes a dysbiosis which promotes reflux of bacteria into the pancreaticobiliary duct and bacterial translocation across inflamed intestines → pancreatitis and reactive hepatitis/neutrophilic cholangitis.
This theory fits best with neutrophilic cholangitis, and potentially local spread of inflammation due to close proximity of SI, pancreas and CBD.

3) SI Inflammation and Autoimmunity: reactive T cells that are generated in IBD due to loss of tolerance express homing markers that result in their localisation to SI, liver and pancreas where exposure to the same antigen → inflammation. The intestinal inflammation may result in increased toxins/antigens/PAMPs reaching portal blood → activation of these reactive T cells causing chronic lymphocytic hepatitis and immune mediated pancreatitis.
Supported by finding that expression of GI lymphocyte recruitment molecules is upregulated in inflammatory liver disease. The immune targeting of bile ducts seen in LC is similar to that seen in human primary sclerosing hyperplasia which is proposed to be caused by an immune mediated mechanism and is associated with IBD
NB: chronic pancreatitis thought to be more due to

Question 43

Laboratory changes with cPSS

Answer 43

• CBC: microcytosis from defective Fe transport and reduced TIBC +/- anaemia. Thrombocytopenia due to reduced TXA/TPO
• Bio: Urea, cholesterol, albumin, glucose all reduced by reduction in functional hepatic mass
• Ammonia sensitivity 81-100% (improved with ammonia tolerance test 95-100%) and is semiquantitative of shunt volume; BATT more sensitive 93-100%. Ammonia tolerance test indicated if normal NH3 with high bile acids or strong suspicion with normal bile acids.
• Coagulation: variably affected,
• Imaging: U/s sensitivity 67-100% (small liver in nearly 100%, 90% bilateral renomegaly); scintigraphy can measure shunt fraction and does not distinguish cPSS from aPSS but is gold standard for excluding presence of shunt. CT dual phase has high sensitivity, angiography now used over portovenography
• Histo: arteriole proliferation, small portal venules and bile duct proliferation. Cannot diagnose PHPV prior to shunt attenuation on biopsies

Question 44

Differences in Feline cPSS presentation and clinical findings

Answer 44

More likely to present with seizures or ptyalism than other signs of HE as well as have postoperative neurological signs. Ammonia sensitivity 83%, specificity 96%, BATT superior sensitivity but specificity 80%.
Should perform biopsy prior to closure of PSS due to presence of congenital hepatic fibrosis which is a contraindication to shunt closure.
Less likely to have reduction in liver size than dogs as is renomegaly and urate urolithiasis.

Question 45

Methods of assessing shunt attenuation and their accuracy

Answer 45

Persistent or recurrent PSS - reported in 20-40% depending on technique and shunt type.
→ biochem 1 month after Sx then wean meds if normal.
Vet Surg 2022: serum fasting NH3 100% specific
Serum MEGX 96% sensitivity
Postprandial BA + MEGX sens 100%, spec 81.5%
→ ultimately still need imaging to confirm.
JVIM 2021 - lignocaine metabolites predict shunt closure with 96% sensitive and 83% specificity.
JVIM 2023 - cPLi not useful to assess closure

Question 46

Medical and Surgical outcomes for IHPSS, EHPSS and cats

Answer 46

Outcome with MX only is poorer than for surgical occlusion. MST 10 months, 50% with due to complications. 33% surviving long term.
Animals >6y at time of presentation of clinical signs may be better managed medically due to higher reported complication rates with surgery.

EHPSS - 22% mortality with surgery reported in early studies in long term (4% perioperative)
JSAP 2022 - good long term outcome in 82%; 68% not needing medication in one study.
JVIM 2019 - metaanalysis of EHPSS treatment found ameroid constrictor superior to thin film band to cause closure.. But overall weak evidence base despite recent publications.

IHPSS - higher risk of intraop haemorrhage and complications. JSAP 2018 - 10% mortality, 85% with partial attenuation had repeat surgery. Outcome better in those with complete attenuation.
Transvenous coil embolisation: emerging interventional procedure which may reduce morbidity and complications of IHPSS. JAVMA 2022 92% 2y survival.

Cats: higher complication rate (30-60%), gradual attenuation is preferred. More likely to have continued neurological sequelae. Often have good clinical outcome despite persistence of biochemical changes.
JVIM 2020 - 34 cats, 6 deaths, 4 persistent seizures
SBA normalised in 25/28
JFMS 2022 - 12 cats, 50% developed seizures 2 died. 88% good long term outcome.

Question 47

what is primary portal vein hypoplasia and what is non-cirrhotic portal hypertension and what are histo fdindings

Answer 47

Insufficient development of the portal venous branches, left portal vein branch or the whole portal venous system.
Lack of portal hypertension in PHPV suggests there is intrahepatic shunting of blood on the microscopic level

NCPH - seen where mAPSS develop due to portal hypertension from portal vein hypoplasia. more often seen in large breed dogs. Can present with ascites and other signs of PH at young age.

Similar histo for both. Lack of portal veins in smaller portal triads. PHPV does not tend to cause portal hypertension while NCPH does.

Question 48

What are ductal plate malformations

Answer 48

Several developmental abnormalities of the portal triad - normally bile ductules develop via epithelial proliferation and resorption of the remaining ductal plate elements
→ abnormal development → persistence of excessive embryonic bile duct structures and varying degrees of fibrosis (unclear why)
→ associated with incomplete development of the portal vein branches (differentiate from PHPV/NCPH by presence of biliary hyperplasia).
→ sinusoidal or perisinusoidal portal hypertension

Question 49

Pathogenesis of HL and Features of cat metabolism that predisposes them to lipidosis

Answer 49

unable to adapt their urea cycle enzymes or aminotransferases to reduced protein intake, cats possess limited ability to adjust protein metabolic pathways for conserving nitrogen

Essential amino acids: taurine, arginine (urea cycle); cysteine, methionine. Latter 2 needed for GSH

Normally FAs enter liver cells and L-carnitine takes to mitochondria → B-oxidation → Krebs cycle. OR they are esterified into TGs and stored in vacuoles or incorporated into VLDL for excretion and use by tissues
In presence of underlying disease:
1) Low insulin levels → decreased LPL in tissues reduces lipid uptake
2) Counter-regulatory hormones increase HSL → more FFAs (peripheral lipolysis) → increased circulating TGs and NEFA → exceeds capacity of B-oxidation → TGs stored in vacuoles (possible L-carnitine and lipoprotein deficiencies as well)
→ hepatocyte steatosis further reduces hepatocellular functions (oxidative damage from reduced GSH)

Concurrent protein deficiency and negative nitrogen balance:
1) Reduced apoprotein production → hepatocyte exportation of TG is slowed (not stopped) and unable to keep up with demand.
2) Lack of arginine for urea cycle causing increased NH3 and thus HE
3) deficiency in GSH due to reduced methionine and cysteine
4) Carnitine production is reduced (relative deficiency) → defective transport of long chain FAs into the mitochondria for B-oxidation

Question 50

Supplements in treatment of feline HL

Answer 50

Supplement B vitamins (B12, thiamine, niacinamide, riboflavin), L-carnitine, Vit E,

IVFT - may require rehydration, correction of acidosis and supplementation of K or PO4.
+/- Mg supplementation

sAME - help replace GSH
Vit K - if prolonged coag times

Question 51

Prognosis for feline HL

Answer 51

Survival rate in idiopathic disease may be better than for those with comorbidity such as pancreatitis or DM.
50-80% overall survival but 20% for those with pancreatitis.
Initial 72h are most critical.
Early aggressive nutrition associated with greater survival

Question 52

Concurrent factors from underlying disease that exacerbate risk of hepatic lipidosis

Answer 52

→ B12 deficiency due to these underlying diseases may exacerbate alterations to metabolism and reduced GSH production.
→ Also has counter-regulatory effects on insulin (antagonism) → FA oxidation due to lack of inhibition of hormone sensitive lipase (HSL) and reduced tissue lipoprotein lipase so reduced uptake.
→ HSL also increased by cortisol, GH, TH, glucagon, adrenaline.

Question 53

Why the change from hepatocutaneous syndrome to Aminoaciduric Canine Hypoaminoacidemia Hepatopathy Syndrome (ACHES)

Answer 53

includes dogs with hypoaminoacidemia and presence of hepatocutaneous hepatopathy features on histopathology WITHOUT superficial necrolytic dermatitis

Loftus JVIM 2022 series of 41 cases demonstrated similar amino acid profiles in these 2 classifications as well as progression to development of SND in 20-30% of cases

Question 54

Theories for pathogenesis/pathophysiology of ACHEs

Answer 54

Causal mechanism of hypoaminoacidemia has not been determined. But this is thought to drive the lesions of the skin and potentially the liver (though it could be that a liver dysfunction results in the hypoaminoacidemia)

Similar SND lesions to those in glucagonomas where it is thought that glucagon role in protein catabolism, gluconeogenesis and promoting insulin secretion results in the development of hypoaminoacidemia
–> lack of specific amino acids (lysine and proline) for collagen synthesis and integrity –> SND (which may require prolonged deficiency to develop and thus be later stage of disease)

wasting aminoaciduria most likely reflected an acquired pathological mechanism of HCS hypoaminoacidemia. However, it remains possible that urine amino acid wasting also might have reflected amino acid depletion from some other cause that subsequently impacted membrane transporters and influenced amino acid homeostasis

Altered glucagon homeostasis may also account for the association of HCS/ACHES with DM

Hyperglucagonemia is an inconsistent finding. Loftus reported normal levels which may be inappropriate in the context of hypoaminoacidemia.
AJVR study reported lower levels of glucagon and GLP1.
this may be complicated by the lack of a standard diagnostic method for measuring glucagon concentrations because multiple molecular glucagon moieties exist in plasma

Question 55

Loftus 2022 Optimal Treatment for ACHES recommendations

Answer 55

> 2 IV infusions with aminoacids +/- lipid

> 3 supplements (sAMe, arginine, ornithine, glutathione, proline, lysine, Omega 3, zinc)

Home cooked diet - able to provide higher dietary protein content than commercial (50% cf 30%) and potentially greater digestibility

MST 1783 cf 214d
Historically <3 months reported

It is highly possible that the early treatment of dogs that had not yet developed skin lesions, was one of the many factors in their improved survival - hence the benefit of ACHES and amino acid profiles for early diagnosis

Question 56

Amino acid deficiency in ACHES and best plasma and urine biomarkers

Answer 56

Arginine, Glycine, Glutamine, Proline, Lysine, Theonine

Plasma 1methyl histadine snes 95%, spec 100%
cystathionine sens 85% and spec 100%
(lower than healthy dogs)

Urine lysine and methionine (normalised to creatinien ratio) higher than controls
Sens 92%, Spec 74%

Question 57

Paraneoplastic syndromes associated with hepatocellular carcinoma

Answer 57

thrombocytosis is thought to occur due to TPO production and Hypoglycaemia from IGF-1

Alopecia in cats

Question 58

Recommended Tx for hepatocellular carcinoma and outcome

Answer 58

thrombocytosis is thought to occur due to TPO production and Hypoglycaemia from IGF-1

Question 59

Cu tox genetics, 3 mutations

Answer 59

Bedlington - COMMD1 assoc with centrilobular accumulation
Reduction in pop over time through selective breeding

ATP7A - Menkes dz, unable to absorb Cu from GIT. Also altered Cu intracellular transport. Xlinked may only be in Labradors
May reduce severity of 7B mutations

ATP7B - Cu transporter involved in excretion into bile, or into plasma by other cells. Autosomal recessive we think
Wilson’s dz in people. Cu accumulation
Mutation identified in Labs, Bedlington (selected for potentially by breeding out commd1), Doberman
Homozygous for mutation not always assoc with Cu excess. Likely affected by diet copper and other Cu transporter function changes