Portosystemic Vascular Anomalies

Portosystemic shunts (PSS) are vascular anomalies that connect the portal system or its tributaries to the systemic circulation [1-3]. Portosystemic shunts may be congenital, in which case they are often singular, or they may be acquired secondary to portal hypertension. Blood shunting through the PSS bypasses the liver, circumventing extraction and detoxification processes normally performed by the hepatocytes. Clinical effects of shunts vary depending on the amount of blood shunted; in severe cases, PSS eventually results in death of the affected animal [4]. To understand the development and effects of PSS, a review of hepatic vascular anatomy and embryology is necessary.

Anatomy of the Hepatic Vasculature and Abdominal Venous Drainage

The portal vein provides up to 80% of blood flow and 50% of the oxygen content to the liver, with the remainder supplied by the hepatic artery. The portal vein is formed by the confluence of the cranial mesenteric vein, which drains the small intestines, and the caudal mesenteric vein, which drains the colon and proximal rectum. Cranially, the portal vein is joined by the splenic vein, which receives blood from the stomach (via the left gastric vein); the spleen; and, in dogs, the gastroduodenal vein, which drains portions of the pancreas, duodenum, and stomach [2,3,5]. The portal vein then bifurcates into the right and left portal veins. Branches of the right portal vein supply the right lateral liver lobe and the caudate process of the caudate lobe. The larger left portal vein gives off a central branch to the right medial liver lobe and a small papillary branch to the papillary process of the caudate lobe before dividing into quadrate, left medial, and left lateral branches [5]. In the cat, the portal vein divides into right, central, and left branches.6 Within the liver lobes, blood flows through the portal venules and percolates through the hepatic sinusoids, mixing with blood from hepatic arterioles. It then collects within the central veins and is transported to the caudal vena cava via the hepatic veins.

Embryologic Development of the Portal System

The veins of the abdominal cavity are derived from the umbilical, vitelline, and caudal cardinal veins of the embryo [7]. The paired vitelline veins form the left hepatic vein, hepatic sinusoids, the hepatic portion of the caudal vena cava, and prehepatic portal vein and its tributaries. Portions of the vitelline and umbilical veins combine to form the ductus venosus and the left branch of the portal vein. The nonportal abdominal drainage, such as the renal and gonadal veins, is derived from the fetal cardinal venous system. The caudal cardinal veins also form the prehepatic caudal vena cava (caudal to the liver) and the azygos vein. In a normal animal, the only communication between the cardinal and vitelline systems is where the prehepatic and intrahepatic segments of the caudal vena cava join. Congenital extrahepatic portocaval and portoazygos shunts are developmental anomalies that result in abnormal, functional communication between these two systems [7]. Numerous nonfunctional portocaval and portoazygos communications are normally present in the fetus; these may become functional if chronic portal hypertension develops [7]. In rare instances, extrahepatic congenital PSS may result from persistence of the umbilical vein [8].

Circulation through the ductus venosus permits at least 50% of the oxygenated blood from the placenta to reach the fetal heart without traversing hepatic sinusoids [9-11]. In most mammals it undergoes functional closure in the first 2 to 6 days after birth and structural closure within a few weeks [9,10,12,13]. The cause of functional closure of the ductus venosus is controversial [13-15]. Decreased portal blood flow and pressure and cessation of umbilical placental flow result in retraction and narrowing at the ductus origin [10]. In newborn puppies, no anatomic sphincter is evident, and the ductus appears to narrow uniformly after birth [7,10,14,15]. Ductus flow is not detectable by Doppler ultrasonography in 50% of Irish wolfhound puppies 4 days after birth and in 100% 9 days after birth [13]. Connective tissue proliferation at the junction of the ductus venosus and umbilical portal sinus in dogs expands to the termination of the ductus at the left hepatic vein, resulting in structural closure within 3 weeks after birth. Persistence of the fetal ductus venosus results in a left-sided intrahepatic PSS. If the ductus venosus remains patent in dogs, it may be secondary to underdevelopment or atresia of the hepatic portal system rather than a failure of primary closure mechanisms [11]. Etiology of central and right-sided shunts has not been determined and it is unknown whether these represent anomalous ductus venosus or other developmental errors.

Congenital Portosystemic Shunts

Etiology

Congenital PSS are reported in 0.18% of all dogs and 0.05% of mixed-breed dogs.

Because Yorkshire terriers, Irish wolfhounds, and a variety of other breeds are at increased risk for PSS, an underlying hereditary cause is suspected [16,17]. Familial relationships have been noted in Irish wolfhounds with PSS, and incidence of the disease has been reduced by breeding outside of these lines [18]. In Yorkshire and Cairn terriers, inheritance is not simple dominant, simple recessive, or sex-linked [17,19]. In humans, a recessive mode of inheritance is suspected for familial patent ductus venosus [20]. Inheritance of PSS in dogs is autosomal and most likely polygenic, or monogenic with variable expression or incomplete penetrance [17,19]. Genetic predispositions have also been noted in other portal vascular diseases, including muscular portal venular hypertrophy with secondary acquired portosystemic shunting in Cocker spaniels and congenital portal hypoplasia (also known as hepatic microvascular dysplasia or HMD) in Cairn terriers [21,22]. Breeding of dogs with HMD can result in offspring with PSS, suggesting that the diseases may be related.

Clinical Signs

Neurologic, urinary, and gastrointestinal signs are reported in animals with congenital PSS. General clinical signs of animals with congenital shunts include small stature, poor hair coat, weight loss, fever, and anesthetic or tranquilizer intolerance [2,3,23-26]. Poor growth may be a result of decreased serum insulin-like growth factors (IGFs), which are anabolic and mitogenic polypeptide hormones that are responsible for prenatal tissue growth and postnatal development [27].

Because of decreased urea production and increased ammonia excretion, animals can present with polyuria, pollakiuria, stranguria, and other clinical signs of urinary tract dysfunction and infection. Polydypsia and polyuria may also result from alterations in portal vein osmoreceptors, decreased renal medullary concentration gradient, potassium depletion, stimulation of thirst centers owing to hepatic encephalopathy, medullary solute washout, decreased responsiveness to ADH, shift in intrarenal blood flow from cortical to juxtaglomerular nephrons, and increased endogenous cortisol concentrations [23]. Animals with PSS may develop renomegaly secondary to increased glomerular filtration rate or changes in renal metabolic function or blood flow [28].

Hepatic Encephalopathy

Pathophysiology

The most common clinical signs in dogs and cats with PSS are neurologic abnormalities associated with hepatic encephalopathy [2,3,23,25,26]. Clinical signs include depression, dementia, stupor, and coma. Muscle tremors, motor abnormalities, and focal and generalized seizures have also been reported [2,29]. The metabolic cause of hepatic encephalopathy is unknown, but is probably dependent on several factors, including alterations in amino acid neurotransmitters γ-amino butyric acid (GABA), glutamate, and glutamine; accumulation of cerebral toxins; and dysfunction of astrocytes [29-46]. Toxins that have been implicated in hepatic encephalopathy include ammonia, mercaptans, short-chain fatty acids, indoles, skatols, aromatic amino acids (AAA), and biogenic amines. None of these factors alone will consistently initiate an encephalopathic coma experimentally, but any may play a part in its development. Other metabolic alterations associated with portal blood shunting and impaired hepatic function include increases in blood levels of epinephrine, adrenocorticotropin, α-melanotropin, and cortisol [46-49]. Consequences of these increases on neurologic function of animals with PSS has not yet been thoroughly evaluated.

Ammonia

Ammonia is a side product of degradation of glutamine by glutaminase in the brain, small intestines, kidneys, and other tissues [33]. Ammonia produced by the small intestines is reabsorbed and transported through the portal system to the liver where 80 to 90% is transformed into urea via the Krebs-Hensleit urea cycle or used in the conversion of glutamate to glutamine [29,32]. Most urea is excreted by the kidneys into the urine; however, 20 to 25% is released into the intestinal lumen where urea and remaining amino acids, amines, and purines are degraded into ammonia by urease-producing coliforms and anaerobes within the colon. In the kidneys, a small portion of the ammonia produced during renal glutamine metabolism is reabsorbed and carried into the systemic circulation via the renal veins. Within skeletal muscle, ammonia is metabolized through glutamine synthesis; this process is coupled with the use of branched-chain amino acids for energy production [32].

Because the brain lacks several enzymes of the urea cycle, ammonia must be removed by glutamine synthesis through amidation of glutamate in the astrocytes. Increased ammonia concentrations in the cerebrospinal fluid may cause neurotoxicity as a result of disturbances in cerebral energy metabolism, alteration in excitatory and inhibitory mechanisms, and interference with neuronal membrane transport and receptor function [34-36]. Structurally, hyperammonemia induces myelin splitting and brain vacuolation, preferentially within the white matter. Histologically, animals with hepatic encephalopathy develop Alzheimer type II cells and polymicrocavitation, particularly in the brainstem, cerebellar nuclei, and the border between grey and white matter [34,39,50].

In people with acute liver failure, venous ammonia concentrations often increase with the severity of clinical signs, and arterial ammonia concentrations greater than 150 µmol/L predict a greater likelihood of dying from brain herniation [35,51]. In animals, the correlation between blood ammonia concentration and degree of encephalopathy is poor. Brain to blood concentration ratios in acute liver failure, however, may be 4 to 8 times normal because of increased ammonia uptake in the brain [36]. Mercaptans and short-chain fatty acids, products of bacterial activity in the intestines, may reduce ammonia metabolism or act synergistically with ammonia to increase inhibitory neurotransmission [33].

Glutamine

In the brain, astrocytes are critical for ammonia metabolism, regulation of the extracellular environment, neuronal excitability, and neurotransmission. Accumulation of intracellular glutamine secondary to hyperammonemia causes osmotic stress and astrocyte swelling. This upregulates expression of peripheral benzodiazepine receptors, affects multiple ion channels and amino acid transport, alters receptor densities and neurotransmitter processing, induces deposition of glycogen and inhibition of glycogenolysis, and increases synthesis of neurosteroids that are potent modulators of neuronal GABA receptor activity [35,36]. Cerebrospinal fluid (CSF) concentrations of glutamine are significantly higher in dogs with PSS compared with healthy dogs fed a low-protein diet [37].

Glutamate

The mammalian brain has four types of excitatory receptors that are defined by agonist selectivity, including N-methyl-D-aspartate (NMDA), α-[3H]amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), kainite, and L-2-amino-4-phosphonobutyrate (L-AP4) [38]. A fifth receptor subtype is linked to phophoinositol metabolism. L-Glutamate, the most important excitatory neurotransmitter, acts preferentially at AMPA and kainite sites. Effects of L-aspartate, another excitatory neurotransmitter, are thought to be mediated predominantly through the NMDA receptor. In dogs with congenital PSS and hepatic encephalopathy, glutamate concentrations are increased 65% in the CSF [30,39]. Kainate-receptor density and low-affinity AMPA sites are reduced, however, which may result in decreased excitatory neurotransmission and, therefore, a predominance of inhibitory neurotransmission [38].

Gamma-Aminobutyric Acid (GABA)

Gamma-aminobutyric acid, the most important inhibitory neurotransmitter, is produced by enteric bacteria and is usually metabolized by the liver. Binding of GABA to its receptors increases chloride flow into the neuron, resulting in membrane hyperpolarization and inhibition of neurotransmission. The GABA receptor also has binding sites for barbiturates, benzodiazepines, and benzodiazepine-like substances called ligands. The majority of studies have found no significant alteration in brain GABA-receptor density or affinity in animal models of hepatic encephalopathy, and GABA concentrations are within normal range in dogs with congenital PSS [30,38,39]. Some researchers suggest, however, that ammonia may enhance selective binding of GABA to receptors, increase synaptic availability of GABA by inhibiting synaptic uptake, and upregulate peripheral-type benzodiazepine receptor release of neurosteroids that are potent agonists of GABA receptors, thus increasing inhibitory neurotransmission [40].

Peripheral-type Benzodiazepine Receptors

Because GABA receptors contain binding sites for endogenous benzodiazepine receptor ligands, benzodiazepines were originally speculated to produce central nervous system (CNS) depression in animals with hepatic encephalopathy [26]. Although dogs with congenital PSS have increased concentrations of endogenous benzodiazepine receptor ligands in peripheral and portal blood, they do not have increased benzodiazepine binding activity in the CSF, and infusion of the benzodiazepine receptor antagonist flumazenil has little effect in reversing clinical and neurophysiologic dysfunction of dogs with chronic hepatic encephalopathy [41,52]. However, administration of sarmazenil, a drug that has both antagonistic and partial inverse-agonistic activity, results in significant improvement in electroencephalographic activity and clinical grade of dogs with hepatic encephalopathy [41,42]. Sarmazenil is thought to negatively modulate GABAergic tone by counteracting the actions of ammonia and neurosteroids on the GABA receptor, potentially balancing the effects of decreased excitatory glutamatergic neurotransmission [42].

Unlike central receptors, peripheral-type benzodiazepine receptors have increased density and expression in hepatic encephalopathy models [39]. Ammonia is thought to upregulate these receptors, enhancing the production and release of neurosteroids that are potent agonists of the GABA receptor complex [34,39,40]. Manganese also increases expression of peripheral-type benzodiazepine receptors, resulting in increased inhibitory activity [39].

Amino Acid Imbalances

Aromatic amino acids (phenylalanine, tyrosine, and tryptophan) are normally metabolized by the liver; whereas branched-chain amino acids (valine, leucine, and isoleucine) are used as energy sources in skeletal muscle and as substrates for CNS synthesis of the excitatory neurotransmitters norepinephrine and dopamine [30,33,43,46]. Dogs with PSS have significant increases in plasma concentrations of aromatic amino acids (AAA) owing to reduced hepatic clearance. Additionally, peripheral concentrations of branched-chain amino acids (BCAA) are significantly decreased in response to hyperammonemia, hyperinsulinemia, and hyperglucagonemia, resulting in a reduction of the peripheral BCAA:AAA ratio to 1.5 or less (normal is greater than 3.0) [30,33,43,46]. Hyperinsulinemia decreases the rate of release of BCAA and stimulates the rate of utilization of BCAA by muscle and adipose tissue and incorporation of BCAA into proteins [43]. Because all amino acids compete for the same transport system into the brain, decrease in peripheral concentrations of BCAA means more AAA are transported into the CNS, resulting in reduction of CSF BCAA/AAA ratio to 0.5 (normal, 2.3) [30,43,46]. Increased AAA may result in increased concentrations of inhibitory neurotransmitters and formation of weak or false neurotransmitters that disrupt normal synaptic impulse transmission [37,46,53]. Tryptophan hydroxylation is the rate-limiting step in CNS serotonin synthesis; therefore, increased CSF tryptophan could increase serotonin concentrations and thus inhibitory neurotransmission [37]. Increased tryptophan in the brain may result in increased amounts of its oxidative product quinolinic acid. Quinolinic acid is a known excitotoxin that acts at the NMDA receptor, causing irreversible damage to neurons [44].

Precipitating Factors

Factors that may increase the chance of an encephalopathic episode include protein overload, zinc deficiency, arginine deficiency in cats, hypokalemia, alkalosis, hypovolemia, gastrointestinal hemorrhage, infection, azotemia, and constipation [2-4,29,32,39,42,45,53]. Blood that has been stored for 24 hours contains 170 µg of ammonia/dl; ammonia concentrations increase further with longer storage [29]. Diuretic agents promote hypokalemia, which increases renal ammonia production and alkalosis, increasing the availability of diffusible ammonia [29].

Treatment

Medical management of animals with PSS-associated hepatic encephalopathy includes correction of fluid, electrolyte, and glucose imbalances and reduction of precipitating factors [3,24,28,54]. Reduction of total protein intake is more beneficial than altering the content of dietary amino acids; however, severe protein restriction may result in loss of skeletal muscle mass and subsequent reduction in ammonia metabolism [46,55]. Depletion of zinc can precipitate hepatic encephalopathy, and supplementation may improve psychomotor function in mildly affected patients [56,57].

Lactulose is a poorly absorbed synthetic disaccharide that is hydrolyzed by colonic bacteria to short-chain fatty acids, lactic acid, and hydrogen. Proposed effects of lactulose include decreased colonic pH with subsequent entrapment of ammonium; inhibition of protein and amino acid metabolism, thereby reducing formation of ammonia and amino acid-derived short-chain fatty acids; decreased intestinal transit time; and increased fecal nitrogen excretion [56]. Nonabsorbable disaccharides have not consistently been shown to reduce or prevent signs of hepatic encephalopathy in human clinical trials, but are still used frequently in people and animals with hepatic encephalopathy [58,59]. Administration of nonpathogenic lactic acid bacteria may provide benefits similar to lactulose and may increase the proportion of non-urease-producing bacteria in the intestines [60]. Oral administration of antibiotics will also decrease colonic bacterial populations.

Other medications that improve clinical status of people with hepatic encephalopathy include arginine, sodium phenylacetate, sodium benzoate, L-ornithine L-aspartate, methionine sulfoximine, and sodium benzoate, which decrease ammonia production or increase ammonia metabolism [35,36,44]. L-ornithine L-aspartate (LOLA) may provide substrate to the liver for enhancing the residual urea cycle and serve as a substrate for ammonia detoxification in the muscles [35,61]. Administration of LOLA reduces brain edema in animals with acute liver failure [32]. Methionine sufloximine, an inhibitor of glutamine synthetase, prevents uptake of nonpolar amino acids, including tryptophan, by the CNS, ameliorating signs of hepatic encephalopathy in rats with surgically induced PSS [37]. Mild hypothermia may also be useful to reduce blood-brain ammonia transfer [34].

Laboratory Abnormalities

Hemograms

Abnormalities on hemograms of animals with PSS include anemia, microcytosis, hypoproteinemia, and leukocytosis [2,3,23]. Other reported hemographic abnormalities include target cell formation, poikilocytosis, and hypochromasia. Potential causes of anemia include decreased red blood cell production because of poor nutritional status, low erythropoietin levels, decreased transferrin production and subsequent poor iron utilization, and abnormal cholesterol and lipid metabolism; decreased survival of red blood cells; dilution from increased extracellular fluid and plasma volume and total body water; or chronic loss from parasites or a coagulopathy [2,3,23,28]. Additionally, hematocrits may be considered low according to adult laboratory reference ranges but may be within normal limits for pediatric patients [62]. Microcytosis is thought to occur because of a problem with iron transport or utilization rather than an absolute iron deficiency. Dogs with congenital PSS have decreased serum iron concentrations and normal or decreased total iron binding capacity [63,64]. Some naturally affected animals and those with surgically created portocaval shunts may have accumulation of stainable iron in the liver [63,64].

Presence of leukocytosis is variable and may occur in response to stress, hypercortisolemia, or infection. Inadequate clearance of bacteria and endotoxins from the portal system may play a role in development of leukocytosis; however, significant differences in concentration of endotoxins and in rates of positive portal blood cultures have not been found when comparing normal dogs with those with congenital PSS [65,66]. Recurrent bacterial infections, fever, leukocytosis, and hypergammaglobulinemia may occur with reticuloendothelial impairment, because 90% of reticuloendothelial function in dogs occurs within the liver [67]. Dogs with PSS have significantly impaired reticuloendothelial function secondary to a reduction in effective liver blood flow. Reticuloendothelial activity increases in the spleen and lung, but only partially compensates for the hepatic reductions [67]. Severity of preoperative leukocytosis is correlated with postoperative outcome [68].

Serum Chemistry

In dogs with congenital PSS, decreased blood urea nitrogen and albumin and increased partial thromboplastin time are primarily the result of decreased hepatic production of proteins [23,69]. Hypoalbuminemia may also occur secondary to intestinal loss or fluid retention [64]. Decreased creatinine may occur with hepatic insufficiency or reduced muscle mass; the level of creatinine is also naturally lower in young patients [28]. Potential causes of hypoglycemia include decreased hepatic glycogen stores, increased insulin concentrations, decreased responsiveness to glucagon and insulin, and abnormal balance of counter-regulatory hormones (cortisol and epinephrine) [23,70]. Dogs with congenital PSS have hyperinsulinemia and hyperglucagonemia secondary to insulin hypersecretion, insulin resistance, and decreased hepatic degradation of these hormones. Hypoglycemia is uncommon in cats with PSS, possibly because of their tendency to develop stress-induced hyperglycemia during sampling [23].

Increases in alanine aminotransferase concentrations occur with hepatocellular necrosis and increased membrane permeability, possibly as a result of poor hepatic perfusion and cell hypoxia [23,64] Because cholestasis is not a prominent feature of PSS, an elevation in serum alkaline phosphatase concentrations in young animals may actually be of osseous origin [23].

Urinalysis

Low specific gravity may be secondary to polyuria/polydipsia or to alterations in the renal medullary concentration gradient from deficits in urea [23]. Chronic hypercortisolism induces inadequate osmoregulation of release of ADH and, thus, polyuria [70]. Animals with congenital PSS may have hematuria, pyuria, and proteinuria, and clinical signs of urinary tract infections secondary to urolithiasis or inflammation from urate crystal or calculus that form because of increased ammonia excretion [2,23,24]. Renal urate calculi may dissolve after shunt ligation [71].

Bile Acids

Bile acids are synthesized in the liver from cholesterol. Within the liver they are conjugated to taurine (cats and dogs) or glycine (dogs) to increase their water solubility and enable micelle formation. Conjugated bile acids are excreted across the hepatocyte canalicular membrane into bile. Cholecystokinin, which is released in response to ingestion of a meal, stimulates gallbladder contraction and release of bile acids into the duodenum [72]. At least 95% of intestinal bile acids are actively reabsorbed in the ileum and are transported by portal blood back to the liver (the "enterohepatic cycle"), with the remainder lost in the feces [72-74]. At the sinusoidal surface of the hepatocyte, bile acid uptake relies on a sodium-coupled transporter. Serum bile acid concentrations increase in conditions that affect hepatocellular uptake, such as cholestasis or primary hepatic disease, or conditions that alter vascular flow to the liver, such as PSS. They are not significantly affected by dehydration, hypovolemia, or passive hepatic congestion. Effects of lipemia and hemolysis on spectrophotometric sample analysis of bile acids are unpredictable; theoretically they can overestimate bile acids by scattering light and increasing spectrophotometric absorption. However, lipemia may decrease bile acids by volume displacement of serum, and hemolysis can reduce bile acid recovery [75]. Falsely lowered results may occur with delayed absorption from prolonged intestinal transit time, lack of gallbladder contraction because of inadequate food intake or delayed gastric emptying, or malabsorption/maldigestion with subsequent decrease of enterohepatic recirculation. Postprandial bile acid concentrations are less than fasting in 20% of animals because of spontaneous interdigestive gallbladder contraction or with prolongation of gastric emptying or intestinal transit times [4,23,76].

Increases in postprandial bile acids that were mild (> 31 µmol/L) or moderate to severe (> 80 µmol/L) were reported in 79% and 34% of Maltese dogs, respectively [75]. Most had normal ammonia tolerance tests, and bile acids were significantly lower when measured by high-performance liquid chromatography, indicating that bile acids measured spectrophotometrically in Maltese may be increased by some other cross-reacting substance [75].

Plasma Ammonia Concentration

In dogs with PSS, sensitivity of postprandial ammonia is 91% [6] hours after feeding, compared with 81% before feeding; ammonia tolerance test is recommended to increase sensitivity [77]. Plasma ammonia levels may be normal in dogs with PSS after prolonged fasting or with effective medical treatment [23]. Because erythrocytes contain 2 to 3 times the amount of ammonia in plasma, improper sample cooling, hemolysis, incomplete plasma separation, or delays in sample analysis falsely increase ammonia values. Concentrations of ammonia measured with tabletop analyzers can be falsely increased if ammonia-based cleaners are used nearby or if ammonia-rich skin oils contaminate the apparatus.

Histology

Hepatic histologic changes in animals with PSS include generalized congestion of central veins and sinusoids, lobular collapse, bile duct proliferation, hypoplasia of intrahepatic portal tributaries, Kupffer cell hyperplasia, and proliferation of small vessels and lymphatics [54]. In dogs with surgically created PSS, direct infusion of insulin into the intrahepatic portal vein reduces atrophy, preserves hepatocyte ultrastructure, and increases cell renewal, indicating the first pass effect of insulin may be necessary for liver development [70]. Dogs with PSS have increased fragility of intracellular organelles, increased endoplasmic reticular and lysosomal enzymes, and increases in the biliary canalicular component of alkaline phosphatase activity [78]. Increased hepatic iron stores can be seen in some dogs with congenital PSS but this is not a consistent finding [63,64]. Histopathologic changes in the livers of dogs with congenital PSS are identical to those in dogs with primary hypoplasia of the intrahepatic portal venous system (HMD), reduced portal perfusion for any reason (e.g., portal vein thrombosis), and congenital arterioportal fistula; therefore, histopathology alone may not differentiate among these diseases [22,54,79,80].

Surgery

Surgical options include acute ligation with suture; gradual occlusion with ameroid constrictors, cellophane banding, or hydraulic occluders; or embolization with coils [2,3,81-86]. When suture ligation is performed, portal and central venous pressures are measured to determine the acceptable degree of attenuation, because [32] 60% of animals cannot tolerate complete acute occlusion [3,68,81-85,87,88].

Normal intraoperative portal pressures range from 6 to 15 cm H2O (6-10 mm Hg); portal pressures in animals with PSS range from 0 to 12 cm H2O [2,3,87]. Acute ligation of single PSS in animals with poorly developed or nonexpansile intrahepatic portal vasculature results in large increases in portal pressure and decreases in central venous pressure. Central venous pressure is an indirect measurement of right atrial pressure and cardiac preload. It is controlled by the tone of capacitance vessels and the intrathoracic pressure when right ventricular function is adequate and blood volume is stable. Because blood flow is proportional to the fourth power of vessel radius, small decreases in portal vessel size result in large decreases in venous return and central venous pressure [87]. Increases in portal pressure are caused by increased resistance to blood flow in the hepatic vascular bed. Mild increases in portal pressure accompanied by large decreases in central venous pressure and subjective evidence of portal hypertension during shunt occlusion suggest splanchnic venous compliance has increased and splanchnic pooling has occurred [87,89]. Portal pressure measurements can vary with depth of anesthesia, administration of inotropes, catheter position, abdominal viscera position, abdominal bandages, temperature, hydration status, phase of respiration, degree of splanchnic compliance, and other systemic factors [89].

Multiple Acquired Portosystemic Shunts

Multiple acquired PSS are tortuous vessels that connect the portal system with tributaries of the caudal vena cava, most frequently the left renal or gonadal veins. They are thought to originate from pre-existing nonfunctional communications between the portal vein and the systemic circulation, secondary to portal hypertension from severe liver fibrosis, neoplasia, portal atresia, or congestion [90,91]. Animals with multiple acquired shunts often have neurologic and urinary tract signs similar to animals with congenital shunts [90]. Because of underlying portal hypertension and, in some cases, severe hypoalbuminemia, animals with multiple acquired shunts often develop ascites. Bleeding dyscrasias from decreased hepatic production of coagulation factors may also occur, resulting in prolonged bleeding of wounds and hematoma formation at venipuncture sites. Blood work results vary with the underlying cause but often include hypoalbuminemia, decreased blood urea nitrogen concentrations, increased liver enzymes, and increased bilirubin if cholestasis is present.

Hepatic Arteriovenous Fistulas

Hepatic arteriovenous (AV) fistulas are anomalous connections between the hepatic artery and the portal or hepatic vein. They are most often caused by congenital failure of embryologic vascular systems to differentiate into capillary, arterial, or venous structures; they may also occur as a result of trauma or surgery [92-97]. In animals with hepatic AV fistulas, high arterial pressure flow into the portal system results in retrograde portal flow, with subsequent intrahepatic portal hypoplasia, and portal hypertension with subsequent development of multiple acquired PSS. Clinical signs of hepatic arteriovenous fistula are associated with hepatic insufficiency (diarrhea, vomiting, neurologic abnormalities), portal hypertension (ascites), and decreased arterial blood volume (tachycardia, water-hammer pulses with decreased diastolic pressure, ventricular failure). On physical examination, a systolic cardiac murmur may be noted. Many dogs have water-hammer pulses and an auscultable continuous machinery-type murmur with the point of maximum intensity on the abdominal wall over or near the affected lobe [96]. Biochemical and hemogram abnormalities are similar to those of animals with PSS. Diagnosis of hepatic arteriovenous fistulas is made with Doppler ultrasonography. The presence of an extremely dilated and tortuous portal branch in a liver lobe is considered pathognomonic [94,95,97]. Ascites, hepatofugal blood flow in the portal vein, and multiple acquired shunts may also be noted. On exploratory laparotomy, affected liver lobes have multiple large, tortuous vessels; acquired extrahepatic shunts around the left renal and gonadal veins are also evident. Histologically, the fistulas consist of numerous thick-walled arteries and markedly dilated veins. The arteries and veins may contain smooth muscle hyperplasia, and hepatic lobules are atrophied, especially near the fistulas. Proliferation of bile ductules and thick-walled hepatic arterioles are found in the portal triads; portal veins in the triads may be reduced in size or absent [98]. Surgical ligation of the hepatic arteriovenous fistula or resection of the affected liver lobe will decrease clinical signs caused by arteriovenous shunting in 57% of dogs [3,96]. Animals are pretreated with glycopyrrolate or atropine to prevent reflex bradycardia (Branham reflex) with closure of the fistula.