Congenital hepatic vascular anomalies

Jessica Adamany
December 16, 2016

Normal vascular anatomy

 Caudal vena cava: drains the left and right renal veins as well as the hepatic veins as
it passes through the liver

 Portal vein:
o Carriers 70% of the blood and 50% of the oxygenated blood to the liver
o Drains the splanchnic viscera: spleen, pancreas, stomach, and intestines via
the cranial and caudal mesenteric veins
o At the hilus of the liver it splits into a left and right portal branch which have
branches that terminate in liver at the portal triads. Here the blood travels
though the sinusoids and then enters the central vein hepatic veins
caudal vena cava.
o In the fetal liver the ductus venous connects the portal vein to the systemic
circulation to bypass the liver.

 Hepatic artery:
o Tributary of the aorta
o Carries 30% of the blood and 50% of the oxygenated blood to the liver
Fetal liver circulation
 The ductus venous carries oxygenated blood from the placenta to the fetal systemic
circulation thus bypassing the fetal hepatic circulation
 At birth this vessel closes shortly after birth (days).
 Portosystemic shunting occurs if the ductus venous remains patent or there are
other congenital vascular anomalies, portosystemic shunting occurs.
 Portosystemic shunting results in a lack of trophic factors (mainly glucagon and
insulin) are not presented to the liver to encourage hepatic growth and eventually
leading to hepatic atrophy. Thus resulting in deficient protein production, altered
protein and fat metabolism, and reticuloendothelial dysfunction.

Vascular anomaly classification:

1. Congenital/acquired portosystemic shunts
2. Disorders associated with abnormal hepatic blood flow/portal hypertension
a. Primary portal vein hypoplasia (primary hypoplasia of the portal vein)
b. Primary hypoplasia of the portal vein with portal hypertension
i. Noncirrhotic portal hypertension
ii. Portal vein atresia
3. Disorders of outflow resulting in congestion of the liver
a. Cardiac failure
b. Obstruction or compression of the caudal vena cava downstream to its
connection with the hepatic veins
c. Obstruction of the extra hepatic veins or intrahepatic veins

Portal venous blood delivers substrates (glucose, amino acids, short chain fatty acids, and
ammonia), hormones from the pancreas and neuroendocrine cells of the gut (gastrin,
insulin, glucagon), translocated enteric microorganisms and their toxins, IgA, return of bile
acids after fat digestion, and 70-80% of the livers blood supply with 50% of the oxygen.
The reduction in hepatic blood flow due to a vascular anomaly leads to accumulation of
exogenous and endogenous toxins, reticuloendothelial dysfunction, as well as failure of
normal hepatic function including protein synthesis, gluconeogenesis, glycogenolysis, urea
cycle, and uric acid cycle.
I. Congenital portosystemic shunt
Anatomy:
 Intrahepatic shunts most often originate from the left branch of the portal vein
which is corresponds to the embryological ductus venosus  “portocaval shunt”.
Less commonly they occur from the right branch of the portal vein
 Extrahepatic shunts arise from any part of the portal system and may drain into the
caudal vena cava or azygos vein
 Typically one congenital PSS is present however multiple have been previously
reported (Leeman, JJ et al. Multiple congenital PSS in a dog: case report and
literature review. JAAHA 2013.)

Signalment:
 More common in dogs than cats
 Often notice clinical signs before 1-2 years
 Intrahepatic portosystemic shunts
o More common in large breed dogs
o Higher prevalence in Irish wolfound, golden/Labrador retrievers, Australian
cattle dogs, and Australian shepherds
o Inherited in Irish Wolfhounds
 Extrahepatic portosystemic shunts
o More common in small breed dogs
 Higher odds ratio in yorkie, havanese, maltese, dandi dinmont terrier,
dachshund, pug and min schnauzer
 Hereditary in yorkshire terriers with a 36 times greater odds ratio,
Cairn terriers, and maltese (and potentially the other above breeds)
o More common in cats than intrahepatic
 DSH, Persian, Siamese, Himalayan and Burmese commonly reported

Clinical signs:
 PUPD: possible explanations include poor medullary concentration gradient (lack of
urea), increased renal blood flow, increased ACTH secretion and hypercortisolism,
phychogenic polydypsia from hepatic encephalopathy

 Gastrointestinal signs: anorexia, vomiting, diarrhea, picca

o Occur in 30% of dogs; less common in cats
o 75% of cats have ptyalism

 Dysuria: Secondary to ammonium urate calculi; up to 30% of cases in one study

 Hepatic encephalopathy
 o Usually the result of a PSS (acquired or congenital) to cause HE in dogs as the
reserve capacity of the liver is reported to be enough to prevent HE in liver
disease when there is no collateral circulation
o Worsened by hypokalemia, alkalosis, hypovolemia, gastrointestinal
hemorrhage, high protein meals, etc
o NH3 + H+  NH4+
o Alkalosis results in shift to the left side of the equation resulting in more
absorption of ammonia (only the nonionized form is absorbed)
o Hypokalemia results in movement of H+ ions resulting in alkalosis in the
extacellular fluid and acidosis inside the cell. NH3 moves into the cell and
then becomes ionized and trapped. Ammonia level nay be surprisingly low
despite severe HE.
o Implicated substances: ammonia, short chain fatty acids, aromatic ring amino
acids, GABA (inhib), glutamine and endogenous benzodiazepines (inhib).
o Clinical signs: lethargy, restlessness/pacing, ataxia, head pressing, circling,
seizures, behavioral changes, and blindness.
o In humans the degree of HE is not well associated with ammonia levels
indicating that other neurotoxins are likely involved.

 Other: small stature, failure to thrive, anesthetic/ tranquilizer intolerance, copper

colored irises (cat)

Diagnostics:
Clinical Pathology:
o Haematology:
 Leukocytosis: likely due to antigenic stimulation from decreased hepatic
endotoxin and bacterial clearance
 Microcytosis with or without anemia: (60-70% of dogs and 30% of cats).
Often resolves with correction of the PSS.

 Simpson, K.W. et al. Iron status and erythrocyte volume in dogs with
congenital portosystemic vascular anomalies. JVIM 1997
 Suspected to be a relative iron deficiency rather than absolute iron
deficiency. Possible explanations include abnormal iron transport or
abnormal iron sequestration
 Characterized by a low serum iron, low TIBC (transferrin), and normal
to increased hepatic iron stores

 Frowde, P.E. et al. Hepatic hepcidin gene expression in dogs with

congenital portosystemic shunt. JVIM 2014.
 Hepcidin degrades ferroportin which is found in the intestine and
macrophages allowing transport into circulation. Hepcidin is
increased with increased IL-6.
  As IL-6 is increased in dogs with PSS, it was hypothesized that this
was the cause of the iron deficiency.
 Hepcidin was not significantly significant when measured before and
after surgical attenuation of the congenital PSS despite improvement
in red cell parameters hepcidin dysregulation is unlikely to be the
cause of the microcytosis +/- anemia identified in dogs with PSS.

o Serum biochemistry:
 Decreased hepatic synthesis resulting in: decreased urea (70%),
hypoalbuminemia (50%), hypoglycemia, and hypocholesterolemia
 Mild to moderate increase in liver enzymes (ALT/ALP)

o Manganese:
 Important cofactor for many enzymes in the synthesis of proteins,
carbohydrates and lipids, as well as for mitochondrial superoxide dismutase.
 98% eliminated by first-pass effect in the bile. (only 2% reach the systemic
circulation).
 In humans Mn toxicity results in psychiatric disturbances, gait abnormalities
and cognitive deficits. Due to its hepatic clearance increased Mn have been
found in humans suffering from hepatic insufficiency, decreased portal
perfusion. In humans, a direct relationship among Mn blood concentration,
MRI hyperintensity, and severity of HE has been identified. In addition
treatment with chelation has been successful in humans with Mn toxicity
 Gow, A.G., et al. Whole blood manganese concentrations in dogs with
congenital portosystemic shunts. JVIM 2010.
 Significant difference in Mn concentrations amont dogs with cPSS
compared to dogs with non-hepatic illnesses and healthy dogs
 Mn concentrations were not signivicantly different between dogs with
cPSS on normal vs hepatic diets, intra vs extrahepatic shunts, or in
dogs with signs of HE vs no HE
 Further studies are necessary to assess relevance of Mn accumulation
in dogs with PSS

o Bile acids:
 Synthesized in the liver from cholesterol. Excreted into the bile canaliculi
after conjugation and stored in the gallbladder until released into the
duodenum for fat metabolism and absorption. Reabsorbed in the ileum and
transported in the portal venous system to the liver where they are extracted
with an efficiency of 95%.
 Raised bile acids with PSS occur due to shunting of the bile acids into the
systemic circulation rather than recycling.
 Serum samples taken after a 12 hour fast and 2 hours postprandial.

 Falsely lowered results: Lack of appropriate intake/ delayed gastric

emptying, timing of gallbladder contraction, slow rate of intestinal transport,
degree of bile acid deconjugation by bacteria in the small intestine (less
efficient resorption of deconjugated bile acids), and malabsorption of the
small intestine

 Falsely raised results: inappropriate sample handling, liver disease,

cholestasis, glucocorticoid or anticonvulsant therapy, GI diseases, seizures,
and tracheal collapse.
 (Bauer, N.B, et al. Liver disease in dogs with tracheal collapse.
JVIM 2006). Revealed overall significant difference in bile acids using
stimulation with CCK before and after stent placement, however,
these were not a significantly different at different time points. In
addition bile acids remained well above the reference range

 Post prandial bile acids have high sensitivity- reported at 100% in some
studies
 o Ammonia:
 75% of ammonia is generated in the colon by bacterial metabolism. It is
transported in the portal blood to the liver where it enters the urea cycle to
be made into urea for urinary excretion

 Ammonia tolerance test: Pre and 30min post samples taken after
administration of ammonium chloride via nasogastric tube, oral capsule, or
enema. Sensitivity of 95-100% to detect hepatic insufficiency.
CONTRAINDICATED WHEN PATIENT HAS HEPATIC ENCEPHALOPATHY

 False positives: lack of ornithine transcarbamylase in the cat, arginine

deficiency in the cat, methylmalonic academia, other enzyme deficiencies (ex
argininosuccinase and argininosuccinate synthetase in Irish wolfhounds
puppies), urethral obstruction, urease producing UTI.
 Sensitivity of fasting ammonia varies based on the study and cutoff used. See
studies below.

o Walker, M. Postprandial venous ammonia concentrations in the doagnosis of

hepatobiliary disease in dogs. JVIM 2001.
  Postprandial bile acids measured in dogs with PSS and hepatocellular disease
 Hepatocellular damage: No significant change in ammonia concentration at
any time point.
 Congenital portosystemic vascular anomalies: Significantly higher ammonia
concentrations at 6 hours post feeding. Measurement at 6 hours increased
sensitivity from 81% (fasting) to 91% (6 hours post prandial)

 Gerritzen-Bruning, M. J. et al. Diagnostic value of fasting plasma ammonia and bile

acid concentrations in the identification of portosystemic shunting in dogs. JVIM
2006.
 Cases divided into two groups (congenital- PSS, PHPV, AV fistula and acquired
shunting vs no shunting). Cutoffs used were: Ammonia 46 umol/L and BA 6
umol/L
 Fasting ammonia for shunting (congenital and acquired): sensitivity 98%,
specificity 89%
 Fasting bile acids for shunting: sensitivity 89%, specificity 68%
 When only evaluating dogs with liver dysfunction the specificity of ammonia
remained high at 89% while that of BA was significantly lower at 18%

o Ruland, K. et al. Sensitivity and specificity of fasting ammonia and serum bile
acids in the diagnosis of portosystemic shunts in dogs and cats. Vet Clin Path.
2010.
 Animals: clinical signs suggestive of hepatic disease or HE (included animals
with extrahepatic disease)
 Cutoffs: Ammonia: 59 umol/L, Bile acids 20 umol/L
 Dogs (based on above cutoffs):
 Ammonia for shunting: sensitivity 85%, specificity: 86%
 Bile acids for shunting: sensitivity 93%, specificity 67%
 Cats (based on the above cutoffs):
 Ammonia for shunting: sensitivity 83%, specificity 76%
 Bile acids for shunting: sensitivity 100%, specificity 71%
 Optimal cut-off points to diagnosis PSS:
 Dogs: Ammonia: 57umol/L (sensitivity 91%, specificity of 84%), BA: 58
umol/L (sensitivity 78%, specificity 87%)
 Cats: Ammonia: 94 umol/L (sensitivity unchanged, specificity 86%), BA:
34 umol/L (sensitivity unchanged specificity 84%)

o Protein C
 Dogs with congenital PSS have significantly lower protein C activities than
dogs with PHPV
 95% of animals with PHPV have protein C  70% while 88% of dogs with
congenital PSS have protein C < 70%. (Toulza, O. et al. Evaluation of
 plasma protein C activity for detection of hepatobiliary diease and
portosystemic shunting in dogs. JAVMA 2006.)
 Improvement in protein C activity postoperatively

o Urinalysis:
 Isothenuria to hyposthenuria (50%)
 Ammonia biurate crystalluria/ stones (11-58%)
 Hyperammonnuria and hyperuricacidemia

 Caporali, E. H. G, et al. Risk factors for urolithiasis in dogs with

congenital extrahepatic portosystemic shunts in 95 cases (1999-2013).
JAVMA 2015.
 Dogs with portoazygos shunts did not have significantly increased
odds for urolithiasis
 Male dogs, dogs older than >0.9 years, and those treated medically
were at increased risk for the development of urolithiasis

Imaging:
o Abdominal ultrasound
 Sensitivity 74-95%, specificity 67-100%, with a higher sensitivity for
intrahepatic shunts
 PSS, microhepatics, renomegaly, nephroliths/cystoliths
 Portal vein: caudal vena cava ratio < 0.65 (extrahepatic shunts)

o CT
 Gold standard to diagnose PSS in humans
 Sensitivity 96%, specificity 89% in dogs with accuracy in determining the
origin and insertion of the shunt
 5.5 times more likely to determine the presence of absence of a PSS
compared to abdominal ultrasound. (Kim, S.E., Comparison of computed
tomographic angiography and ultrasonography for the detection and
characterization of portosystemic shunts in dogs. Vet Rad & Ultrasound.
2013)

o Scintigraphy
 Transcolonic or transplenic using technetium 99m
 If injected into the spleen can determine where the shunt terminates,
number of shunts and whether they are congenital or acquired. This is not
possible with transcolonic scintigraphy
Treatment: Medical vs. Surgical
Medical
 Diet:
o Dietary protein restricted moderately to reduce the substrates for ammonia
formation by colonic nacteria
o Calulate caloric requirement based on ideal body weight
o Ideal components (on a dry matter basis):
 Carbohydrates: 30-50% easily digested, complex soluble
carbohydates
 Fat: 15-30% and 20-40% for dogs and cats respectively
 Protein: Restrict to 18-22% in dogs or 30-35% in cats. Liver diets
often contain 14-18% (dog) and 31-32% (cats).
o Previous studies in animal models and humans have shown that less severe
clinical signs and survival with a highly digestible protein source such as
vegetable or dairy origin (lower in aromatic AA)

o Proot, S. Soy protein isolate versus meat-based low-protein diet for

dogs with congenital portosystemic shunts. JVIM 2009.
 Compared two low protein diets: soy vs protein dehydrated poultry
 Plasma ammonia was significant lower after the soy diet compared to
the poultry diet
 HE scores improved with both diets with no significant difference
between the two diets
 Lactulose:
o Disaccharide that is metabolized by colonic bacteria to organic acids thus
acidifying the colonic congents and trapping ammonia in the form of
ammonium in the colon.
o Osmotic affect reduce fecal transit time to limit exposure with bacteria

 SAMe, vitamin E, milk thistle: no studies to prove their effectiveness for

management of congenital PSS

 Antibiotics:
o Decreases GI bacterial numbers to allow reduction in ammonia production
o Metronidazole, ampicillin, and neomycin

 Seizure control:
o Active seizures can be controlled with midazolam (Tobias still uses
diazepam)
o Following acute management of seizures, other anti-epileptics can be used
for maintenance.

o Fryer, K.J. et al. Incidence of portosystemic seizures with and without

levetriacetam pretreatment in dogs undergoing portosystemic shunt
attenuation. JVIM, 2011.
  Dogs with extrahepatic shunts
 42/126 dogs treated with levetriacetam with median duration prior
to surgery being 6.5 days
 No dog treated with levetriacetam had postoperative seizures while
5% of dogs in the untreated group (no anti-consultant treatment) did
seizure. These results were statistically significant.
 Due to these findings it is advised that dogs be administered
Levetriacetam 20mg/kg 18 hours for a minimum of 24 hours before
surgery.

 Other: treatment for clotting disorders with plasma or whole blood, gastrointestinal
ulceration (predisposition in intrahepatic shunts) with proton pump inhibitors,
correction of hypovolemia and correction of hypokalemia

Prognosis:
 Despite many dogs have a good response to medical management alone. Surgical
attenuation has been associated with a significantly improvement survival rate and
lower frequency of ongoing clinical signs. However, some dogs can have a long term
survival with few recurrent clinical signs with medical management alone.

 Greenhalgh, S.N. et al. Comparison of survival after surgical or medical

treatment in dogs with congenital portosystemic shunt. JAVMA, 2010.

 Greenhalgh, S.N. et al. Long-term survival and quality of life in dogs with
clinical signs associated with congenital portosystemic shunt after surgical or
medical treatment. JAVMA, 2014.

II. Hepatic arteriovenous malformations

 Very rare condition
 Etiology: Connection of the hepatic artery (or rarely the gastroduudenal artery, left
gastric artery or phrenic artery) with the portal vein via multiple aberrant shunting
vessels. Results in retrograde flow in the portal vein and significant portal
hypertension.
 Due to the marked hypertension numerous extrahepatic acquired shunts are
opened and 75% of dogs have ascites
 Histopathology: see below
 Treatment: liver lobectomy, ligation of the nutrient artery, or glue embolization of
the abnormal arterial vessels. 75% of dogs need medical management
postoperative due to the presence of acquired shunts.
III. Primary hypoplasia of the portal vein
A. PHPV without portal hypertension
 Previously termed microvascular dysplasia (MVD)
 Often affects extrahepatic (often overlooked) and intrahepatic segments of the
portal veins
 Signalment:
o Similar breeds to those for extrahepatic shunts
o Cairn terriers, Tibetan spaniels, maltese, havanese, Yorkshire terriers,
Norfolk terriers, and minature schnauzers
o Median age 3.25 years at time of diagnosis (often older than dogs with
macroscoptic PSS) due to more subtle clinical signs
 Clinical signs: often asymptomatic, however rarely have neurologic or
gastrointestinal dysfunction
 Clinical pathology:
o High bile acids
o Often hematology, serum biochemistry, and urinalysis are normal
o Protein C >70% in 95% of dogs
 Diagnostic imaging:
o Same as above for congenital PSS but no PSS identified and lower shunt
fraction on scintigraphy
 Histopathology: See below
o Signs of hypoperfusion with no macroscopic shunt
o NOTE: apparently lesions are inconsistent among liver lobes. Advised to
get laparoscopic wedge biopsies from numerous lobes to obtain diagnosis
 Treatment: often no treatment required as asymptomatic

B. PHPV with portal hypertension

 Portal vein atresia
 Non-cirrhotic portal hypertension
 Etiology: Suspected to occur due to severe, diffuse intrahepatic vascular
malformations without cirrhosis leading to portal hypertension and
development of extrahepatic shunts
 Signalment
o Often < 2 years of age
o Large breed dogs: Rottweilers, cockers, and Dobermans are over
represented
 Clinical Pathology:
o Microcytosis
o Raised liver enzymes, bilirubin, and blood ammonia
o Hypoalbuminemia, low BUN
o Abnormal liver function tests: ammonia and bile acids
 Clinical Signs:
 o Same as congenital PSS but often with ascites
 Ultrasound:
o Microhepatica
o Portal hypertension (ascites, acquired shunts, hepatofugal flow in
portal vein) with a patent portal vein
 Histopathology: see below
 Treatment: Similar to medical management for PSS but also treatment for
ascites

 Bunch, S.E. et al. Idiopathic noncirrhotic portal hypertension in dogs: 33

cases (1982-1998). JAVMA, 2001.
o Diagnosis made if signs of portal hypertension and histopathology shows
signs of portal vein hypoperfusion
o Prognosis generally favorable (mean 2.9 years)

Histopathology of liver hypoperfusion:

 Similar features with all diseases resulting in hypoperfusion of the portal vein such
congenital PSS, intrahepatic arterioportal fistulas and portal vein obstruction.
Degree of changes depends on severity of hypoperfusion
 Decreased portal vein diameter or complete absence of portal vein, increased
arterioles (response to hypoperfusion) in the portal tracts, increased biliary duct
proliferation, hepatocellular atrophy, Iipogranulomas, increased lymphatics.
 Varying amounts of portal fibrosis
 With PHPV vascular changes are mild and there is no to minimal corresponding
portal fibrosis. Apparently changes can vary between liver lobes
 Non-cirrhotic portal hypertension often has more significant fibrosis extending into
the parenchyma along the portal tracts or bridging between other portal tracts.
There is a lack of inflammation and regenerative nodules.
 Hepatic arteriovenous malformations should have dilated portal venules and
marked arteriolar hyperplasia, with intimal and medial fibro-elastosis and smooth
muscle hypertrophy. If biopsies were taken from areas distant to the malformation,
histiologic changes consistent of portal vein hypoperfusion are often identified
resulting in a potential misdiagnosis.