What's new with congenital PSS? (Proceedings)

Congenital Portosystemic Shunt

Portosystemic shunts (PSS) are vascular communications between the portal and systemic venous systems that allow portal blood to access the systemic circulation without first passing through the liver. Signs of hepatic encephalopathy (HE) dominate the clinical picture because of inadequate hepatic clearance of enterically-derived toxins. Decreased hepatic blood flow and lack of hepatotrophic factors result in hepatic atrophy. Urate urolithiasis, an important complication of PSS, occurs because of increased urinary excretion of ammonia and uric acid. Urolithiasis may be a complication in as many as 50% of animals with congenital PSS. Portosystemic shunts in dogs and cats can be either congenital or acquired. The congenital form is most commonly recognized. Congenital PSS are anomalous embryonal vessels that usually occur as single shunts and are not associated with portal hypertension. Yorkshire terriers are the most commonly reported breed with congenital PSS. Affected lines of Irish wolfhounds and Cairn terriers have also been described. The genetic basis for congenital PSS is unknown, although in Yorkshire and Cairn terriers, inheritance is not simple dominant, simple recessive, or sex-linked. Acquired PSS, which form in response to portal hypertension, are typically multiple extrahepatic shunts connecting the portal system and the caudal vena cava.

Congenital PSS are typically single and may be intrahepatic or extrahepatic. Single intrahepatic PSS are most common in large and medium-sized breeds. Single extrahepatic PSS are more common in cats and small or toy breed dogs. In rare instances, 2 or more vascular communications may be present. Portoazygous or portophrenic shunts may be associated with less severe clinical signs, and consequently, may not be diagnosed until later in life. Dogs with intrahepatic shunts have more severe signs at an earlier age, probably related to the larger volumes of blood diverted through the shunt as compared to extrahepatic shunts. In dogs and cats with congenital PSS, the liver is grossly small and often mottled in appearance. Liver biopsy most consistently reveals hepatocyte atrophy with small or absent portal veins and arteriolar hyperplasia, although biopsy abnormalities may be subtle. Biopsy findings are typical for decreased portal vein flow and are indistinguishable from findings in congenital portal vein hypoplasia (see following section). Liver biopsy findings at the time of surgery do not predict long-term outcome in dogs undergoing surgical correction of PSS.

Congenital PSS occur more commonly in purebred than in mixed breed dogs. Breeds at increased risk include Yorkshire terrier, Miniature schnauzer, Irish wolfhound, Cairn terrier, Maltese, Havanese, Dandie Dinmont terrier, Pug, Australian cattle dog, Golden retriever, Old English sheepdog, and Labrador retriever. In contrast, mixed breed cats are affected more commonly than purebred cats. Of the affected purebreds, Persian, Siamese, Himalayan, and Burmese cats appear to be at increased risk. Age is an important diagnostic clue since most animals develop signs by 6 months of age. A congenital PSS should still be a diagnostic consideration in middle-aged or older dogs, since signs may be subtle and some dogs with congenital PSS go undiagnosed until as late as 10 years of age. This is especially true for dogs with urate urolithiasis, who may not have an obvious history of HE. Miniature schnauzers are more likely to be diagnosed at an older age than are dogs of other breeds.

Clinical signs of congenital PSS are referable to the central nervous system, gastrointestinal system, or urinary tract. Signs of HE usually predominate. The most consistent signs of HE are often subtle such as anorexia, depression, and lethargy. Other common findings indicative of diffuse cerebral disease include episodic weakness, ataxia, head-pressing, disorientation, circling, pacing, behavioral changes, amaurotic blindness, seizures, and coma. Bizarre aggressive behavior, seizures, and blindness appear more likely in cats. Hypersalivation is a prominent sign in cats, but also occurs in dogs. Clinical signs of HE tend to wax and wane and are often interspersed with normal periods, reflecting the variable production and absorption of enteric products that are neurotoxic. Signs of HE may be exacerbated by a protein-rich meal, gastrointestinal bleeding associated with parasites, ulcers, or drug therapy, or administration of methionine-containing urinary acidifiers or lipotrophic agents. Clinical improvement in HE after fluid therapy is common and most likely attributed to correction of dehydration and promotion of urinary excretion of ammonia and other toxins. Improvement from broad-spectrum antibiotic therapy reflects the effect of antibiotics on the toxin-producing intestinal flora. Gastrointestinal signs of intermittent anorexia, vomiting, and diarrhea are common non-specific features of hepatic dysfunction and are not necessarily accompanied by overt signs of HE. Dogs with intrahepatic PSS are at increased risk for GI ulceration and inflammation. Many affected animals have a history of stunted growth, failure to gain weight compared to unaffected littermates, or weight loss. Polydipsia and polyuria are common in dogs but not in cats. If urolithiasis is a complicating feature, pollakiuria, dysuria, and hematuria may occur. Some animals are primarily presented for evaluation of urolithiasis without obvious HE or gastrointestinal signs. A history of prolonged recovery after general anesthesia or excessive sedation after treatment with tranquilizers, anticonvulsants, or organophosphates can be attributed to impaired hepatic metabolism of these substances. Physical examination may be unremarkable except for small body stature or weight loss. The neurologic examination is normal, or if overt signs of HE are present, neurologic findings are consistent with diffuse cerebral disease. Many affected cats have copper-colored irises. Ascites and edema are rare findings unless a congenital PSS is complicated by hypoalbuminemia (<1.0 gm/dl) from GI bleeding or severe dietary protein restriction. Ascites is more likely with portal vein hypoplasia that is accompanied by portal hypertension (see below).

A congenital PSS should be considered in 1) any young animal with intermittent CNS, gastrointestinal, or urinary tract signs, 2) any dog (except Dalmatians) or cat with urate urolithiasis, or 3) dogs and cats of any age with clinical and biochemical evidence of hepatic insufficiency (especially HE) and absence of histologic evidence of severe intrahepatic disease. Although a congenital PSS may be highly suspected based on historical, physical, laboratory, and radiographic findings, a definitive diagnosis requires identification of a shunt by contrast radiography, CT angiography, transcolonic portal scintigraphy, ultrasonography, or exploratory laparotomy. In young animals with consistent clinical features of a congenital PSS but without a demonstrable shunt on portography or portal scintigraphy, portal vein hypoplasia should be considered.

Routine biochemical test results often reflect a pattern suggesting hepatocellular dysfunction in the absence of significant cholestasis or hepatocellular necrosis. Hepatocellular dysfunction is suggested by hypoproteinemia, hypoalbuminemia, hypoglobulinemia, hypoglycemia, decreased BUN, and hypocholesterolemia. Total serum bilirubin concentration is typically normal. Serum liver enzyme activity (ALP, ALT, and AST) is normal to mildly (2 or 3 times) increased, consistent with a lesion of hepatic atrophy and minimal hepatocellular injury or intrahepatic cholestasis. Hematologic findings include erythrocytic microcytosis, target cells, poikilocytosis (especially cats), and mild nonregenerative anemia. Isosthenuria or hyposthenuria are frequently detected on urinalysis. Ammonium biurate crystals are a common finding on urine sediment examination and are an important clue to underlying liver disease. If urolithiasis is a complication of congenital PSS, additional findings may include hematuria, proteinuria, and pyuria. Prolonged coagulation times (prolonged PTT with normal PT) are a common in dogs with PSS, but spontaneous bleeding is unusual. Measurement of plasma protein C activity, which reflects liver function, has been used to help distinguish congenital PSS from MVD.

Serum bile acid concentrations should be performed to document hepatic dysfunction in dogs and cats suspected to have congenital PSS. Fasting SBA are often increased but can be normal since during prolonged fasting, the liver may eventually clear the bile acids from the systemic circulation. Postprandial SBA are usually abnormal (typically exceeding 100 umol/L), although false negative results have been reported. Postprandial SBA remain a good screening test for animals suspected to have PSS. If postprandial SBA concentrations are consistently in the normal range, a diagnosis of congenital PSS is unlikely. Measurement of urine bile acids is less sensitive than serum bile acids for detection of liver disease. Hyperammonemia is a common finding in dogs and cats with PSS, although fasting blood ammonia concentration may be normal.

Survey abdominal radiographs are often performed in animals with suspected PSS to evaluate for microhepatica or presence of urinary calculi, and to investigate other causes of gastrointestinal or urinary tract signs. Ammonium urate calculi are not usually visible on survey radiographs unless they also contain substantial amounts of magnesium and phosphate. Additional radiographic imaging techniques, such as ultrasonography, contrast portography, or transcolonic portal scintigraphy can provide important information about the presence, location, and type of PSS. Ultrasonography is a useful non-invasive method to evaluate animals with suspected congenital PSS. Intrahepatic PSS are more reliably detected with this procedure than are extrahepatic PSS. The kidneys and bladder should also be routinely scanned to detect urate urolithiasis. Computed tomographic angiography (CTA) appears promising as a non-invasive, rapid imaging technique that provides images of all portal tributaries and branches after a single peripheral venous injection of contrast. Images can be reconstructed and manipulated afterwards for further evaluation. CTA is especially helpful in planning surgical or interventional radiologic approaches to the treatment of intrahepatic shunts.

Medical management of HE in dogs and cats with congenital PSS is indicated prior to anesthesia and definitive surgical correction. The cornerstone of therapy is a diet that is moderately protein-restricted with the bulk of calories derived from carbohydrates and fat. Vegetable (soy protein) and dairy (cottage cheese, yogurt) proteins are preferred. Meat and egg proteins are poorly tolerated. The recommended dietary protein intake on a dry matter basis for patients with HE is 18-22% (dogs) and 30-35% (cats). The protein content of the diet should be increased to the maximum amount tolerated without signs of HE. Dietary supplementation with soluble fiber (psyllium 1-3 tsp/day), appears to be beneficial in managing HE via similar mechanisms as lactulose and may allow higher levels of dietary protein to be tolerated. Lactulose, a non-metabolizeable disaccharide, acidifies colonic contents (causing ammonia trapping), shortens intestinal transit time, alters colonic flora, promotes incorporation of ammonia into bacterial proteins, and reduces production of potentially toxic SCFA by producing the nontoxic SCFA acetate. The dose is 0.25-0.5 ml/kg PO q8-12 hrs to achieve 2-3 soft stools per day. It can be safely given on a long-term basis. Antibiotics such as neomycin (22 mg/kg PO, q 8-12 hrs), amoxicillin (22 mg/kg PO q 12 hrs), or metronidazole (7.5 mg/kg PO, q12 hrs) are commonly used to alter the urease-producing intestinal bacterial population. The author no longer recommends neomycin on a longterm basis, because of the possibility of GI absorption when the mucosa is compromised (ulcers, hemorrhagic gastroenteritis), resulting in systemic ototoxicity and nephrotoxicity. Medical management can result in long-term survival, but results of a recent large study supports the widely held belief that surgical treatment is preferable to medical therapy for longterm survival. However, early surgical intervention is not essential, and medical therapy appears to be an acceptable first-line option.

Surgical treatment is recommended in most patients to improve longterm outcome. The best prognosis occurs for extrahepatic shunts, a completely occluded shunt, and for dogs with urate urolithiais in the absence of hepatic encephalopathy. Intrahepatic shunts are technically more difficult to correct surgically. Total surgical ligation of a single congenital PSS is preferred, however, in many cases, only partial (60 to 80%) ligation of the shunt can be safely performed because of the risk of portal hypertension (PH). Portal hypertension occurs after acute shunt ligation, because the intrahepatic vasculature cannot accommodate the additional volume of portal blood which is diverted back to the liver. Gradual shunt occlusion can be accomplished with an ameroid constrictor or cellophane banding. The ameroid constrictor is a specialized device consisting of hydroscopic casein material in a stainless steel ring. The device is surgically placed around the shunt and as fluid is absorbed, the lumen of the ring becomes progressively smaller, causing shunt occlusion. Advantages of ameroid placement include gradual progressive occlusion of the shunt over a 2-3 week period (thus preventing acute post-operative PH), decreased surgical and anesthesia time, and lack of need to monitor portal pressures during surgery. As many as 18% of dogs may have seizures or status eptilepticus that develops up to 96 hours after surgical shunt ligation. The pathogenesis is obscure but seizures do not appear to be caused by simple hypoglycemia or HE. Seizures are treated with diazepam, correction of hypoglycemia, and lactulose for possible HE. A propofol CRI has been recommended for uncontrolled seizures. The prognosis for recovery is guarded.

Transvenous coil embolization (Interventional Radiology) appears promising for management of intrahepatic shunts. Complication rate is low (5%) and includes coil migration, excessive bleeding, aspiration during induction of anesthesia. Severe GI ulceration (recognized both before and after the procedure) has been identified as a significant risk factor for long-term survival. Life-long control of acid secretion has been effective in decreasing this complication. Interestingly, refractory seizures that are described as a complication of surgical shunt ligation, have not been reported with transvenous coil placement.

Prognosis after surgery (ameroid, ligation, or cellophane banding) for extrahepatic PSS is good to excellent in 84%-94% of dogs. A protein-restricted diet and lactulose are usually continued immediately after surgery. Routine biochemistries, including albumin and SBA, are monitored at 3, 6, and 12 months post-op. Most dogs continue to have mildly increased SBA. The necessity for continuation of medical management for HE (low protein diet, lactulose, antibiotics), can only be determined by tapering/discontinuing each therapy individually, and monitoring the clinical response for relapse of signs of HE. From a nutritional standpoint, it would be preferable to provide a moderate amount of dietary protein and continue with lactulose, rather than giving a low protein diet without additional medications. For cats, a good to excellent outcome is reported in 66%-75% undergoing ligation; 33%-75% undergoing ameroid constrictor placement, and 80% undergoing cellophane banding. Cats are more likely to have post-operative complications (up to 75%). The most common complication is neurologic dysfunction including generalized seizures (8%-22%) and central blindess (44%). Blindness usually resolves within 2 months after surgery.

Congenital Portal Vein Hypoplasia (Hepatic Microvascular Dysplasia [MVD], Non-cirrhotic Portal Hypertension [NCPH])

Congenital portal vein hypoplasia (which includes MVD) is a microscopic pathologic malformation of the hepatic vasculature, which occurs in the absence of a macroscopic portosystemic shunt. Histologic features represent the stereotypical response to portal hypoperfusion (small or absent portal veins, compensatory arteriolar hyperplasia, hepatocellular atrophy, lipogranulomas, and sinusoidal dilation). These liver biopsy findings are identical to those described for congenital PSS, experimentally-created portocaval shunt (Eck's fistula), hepatic microvascular dysplasia, portal vein hypoplasia, non-cirrhotic portal hypertension, portal vein obstruction, and arterioportal fistula. Hypoplasia of the portal system is believed to be the underlying developmental abnormality in the clinically diverse disorders of MVD, portal vein hypoplasia and NCPH. Consequently, the WSAVA Standardization group has recommended that the term MVD be abandoned in favor of the term Portal Vein Hypoplasia (PVH), which would also encompass NCPH. However, there is wide variation in clinical features, depending on the severity of hypoplasia of the portal system and the resulting portal hypertension. The author makes a distinction between these two clinical syndromes by referring to PVH without portal hypertension as PVH:MVD and PVH associated with portal hypertension as PVH:NCPH. Dogs with PVH:MVD do not have portal hypertension and are often asymptomatic whereas dogs with PVH:NCPH have clinical features reflecting portal hypertension and multiple PSS.

The relationship between PVH and congenital PSS is unclear, but the increased incidence of PVH:MVD in breeds such as Cairn terriers and Yorkshire terriers that are also at increased risk for PSS, suggests they may be varying expressions of a more general portal vascular malformation. A polygenic mechanism of inheritance for PVH:MVD is suspected in Cairn terriers. Breeding of dogs with PVH:MVD can result in puppies with congenital PSS, suggesting the two disorders may be related. Concurrent PVH:MVD and congenital PSS may explain why SBA concentrations do not return to normal in some dogs despite complete surgical shunt ligation. It may also be responsible for the inability to completely ligate a shunt without incurring portal hypertension, or the development of multiple PSS after shunt ligation. Dogs with PVH:MVD tend to be older at presentation than dogs with congenital PSS. Clinical signs are not consistently seen. This is especially true for Cairn terriers with HMD who are clinically normal. In more severely affected dogs, signs are similar to those seen with congenital PSS but generally milder. Physical examination is often within normal limits. Dogs with PVH:MVD have modest increases in SBA concentrations. Hyperammonemia and ammonium biurate crystaluria rarely develop. The liver is usually normal in size. Bladder or kidney calculi are uncommon. Imaging studies including trans-splenic portal scintigraphy no not reveal a macroscopic shunt. Asymptomatic dogs not require treatment. Medical management of HE may be instituted as needed. The long-term prognosis is excellent.

Suggested Reading: Berent AC et al. Vet Clin North Am 39:513-541, 2009; Tobias KM. Kirk's Current Vet Therapy XIV, 581-586, 2009; Greenhalgh SN et al. JAVMA 236:1215-1220, 2010.