Hepatic Vascular Disorders: What Do We Mean?

A number of hepatic vascular disorders are described in small breed dogs, most involving abnormal development of the portal vein. While extrahepatic congenital portosystemic vascular anomalies (PSVA) have received the most attention, the most common congenital vascular abnormality is microvascular dysplasia (MVD). Histologically, MVD is indistinguishable from PSVA, yet MVD encompasses a number of histologic peculiarities in addition to diminished portal venous perfusion. Along with PSVA, MVD appears to be an inherited abnormality in certain terrier-type dogs. Portal atresia describes a congenital absence of perfuseable extrahepatic or intrahepatic portal vasculature. A veno-occlusive lesion associated with MVD/PSVA is recognized in some breeds. Non-cirrhotic portal hypertension, histologically indistinguishable from PSVA and MVD, occurs more commonly in large breed dogs, and is associated with portal hypertension and APSS. This lesion has at times been mislabeled hepatoportal fibrosis. Hepatic arteriovenous fistulas are bizarre malformations representing the merging of branches of the hepatic artery and portal vein. This lecture will present a synopsis of diagnostic and clinical features of vascular syndromes in small breed dogs as well as their managerial approaches and treatment successes.

Portosystemic Vascular Anomalies (PSVA)

Without question, this disorder is the most common hepatic topic in the veterinary literature from both a diagnostic and therapeutic perspective.

Typical Historical & Clinicopathologic Features: Dogs with a symptomatic PSVA usually present during the first 2 years of life. Many are stunted and intermittently display neuroencephalopathic signs consistent with hepatic encephalopathy (HE), polyuria / polydipsia, episodic inappetence or pica, or vague gastrointestinal signs. Some dogs present only for development of ammonium biurate urolithiasis. However, not all dogs are overtly symptomatic. Some are discovered later in life when liver function tests or abdominal ultrasonography "discover" and abnormality. We really do not know how many PSVA dogs are asymptomatic. Current work suggests that at least 20% of dogs may lack clinical signs notable by an owner. Some PSVA bitches (unligated) have repeatedly produced litters. The most common routine clinicopathologic features include RBC microcytosis, a borderline anemia, a low BUN and creatinine, low glucose (very young toy breed dogs), normal or modestly increased (up to 3-fold) liver enzymes, normal or modestly reduced albumin, hypocholesterolemia, low urine specific gravity (Pu/Pd) and ammonium biurate crystalluria. Urine sediments from at least 3 urine samples collected at different times of the day (especially several hours after eating) are needed to rule out ammonium biurate crystalluria. No routine hematologic, biochemical, or urine assessments are abnormal in every case.

Liver Function Test: Most dogs with PSVA are initially identified with high serum bile acid (SBA)or blood ammonia concentrations. Paired SBA (12-hr fasted and 2-hr postprandial (PSBA)) have a 100% sensitivity for PSVA detection. SBA are considered the most clinically convenient and sensitive liver function assessment (reflect abnormal perfusion or cholestasis) that can be routinely managed and mailed for analysis. Blood ammonia concentrations also have high sensitivity for detecting PSVA but samples must be immediately stored on ice, and rapidly analyzed. In some cases, a provocative ammonia challenge (NH₄Cl, ammonia tolerance test, (ATT)) is necessary to demonstrate ammonia intolerance. Both fasting ammonia and fasting or "random" SBA concentrations have each failed to detect some PSVA dogs; provocative testing with either test (PSBA, ATT) produces abnormal values. A recently developed urine bile acid test is now being used to screen high risk dogs for PSVA and MVD (urine collected 4-8 hrs after feeding). Improved differentiation of PSVA from MVD can be achieved inexpensively and noninvasively by measurement of Protein C; low values are found in dogs with "severe" shunting (MVD dogs usually have normal values.)

Liver Histology: Histologic lesions in PSVA include hepatic lobular atrophy, juvenile portal triads, portal triad arteriolarization (increased arterial cross sections), lymphatic distention in portal triad adventitia and surrounding large hepatic venules, inconspicuous portal venules, and prominent smooth "throttling" hepatic venule musculature. These features also are associated with MVD. Histopathologic features are difficult to identify in small hepatic core biopsies. Liver biopsy is not definitive for syndrome classification and must be combined with imaging studies or Protein C. Biopsy rules out acquired liver disease as an underlying cause.

Definitive Imaging: Until recently, the definitive gold standard for PSVA diagnosis was portovenous venography, with portography completed in right and left lateral and ventrodorsal recumbency. PSVA have been missed when only a single lateral or VD image was recorded.

Ultrasonography: Ultrasonography can detect "classic" features: small liver, hypovascular intrahepatic portal system, large kidneys, uroliths, and in 60 to 90% of cases (depending on ultrasonographer skill) identification of an aberrant shunting vessel. Doppler color flow interrogation identifies PSVA associated turbulence in the vena cava. Otherwise, a slow, tedious, systematic search of the portal vasculature is required.

Nuclear Scintigraphy Studies: Noninvasive detection of PSS is achieved with colorectal scintigraphy; a small amount of technetium pertechnetate (^99m) is placed in the colon with portal uptake/delivery (liver:heart) recorded in real-time with a gamma camera. A shunt fraction (high operator variability) usually > 50% (normal < 15%). A more quantitative but invasive procedure involves injection of ^99mTc-macroaggregates in a splenic vein (US guidance).

Multisector CT Imaging of the Portal Vasculature: Definitively distinguishes PSVA (exact position of aberrant vasculature) and APSS. Images can be obtained in heavily sedated animals in less than 2 minutes, with vascular structures distinguished by peripherally administered nonionic iodinated contrast.

PSVA Treatment: Medical & Surgical: According to the veterinary literature, surgical attenuation of PSVA is the treatment of choice. However, depending on the procedure used and surgical expertise, a 15% to 30% mortality may be realized with persistent shunting in up to 50-60% of cases. A variety of methods have been investigated including partial or complete PSVA occlusion using: silk ligation, ameroid constrictors, cellophane banding, and thrombotic coils. Outcome studies are difficult to compare owing to different surgical procedures, follow-up intervals, and tests. What is clear is that despite an impression of complete surgical ligation, many dogs continue to shunt, that incomplete ligation can remarkably improve symptomatic dogs, and that SBA concentrations inconsistently normalize. While there is an impression that PSVA cannot be managed medically, we have managed a number of minimally symptomatic dogs long term with a prescription veterinary diet formulated for dogs with hepatic insufficiency. Combination of dietary management with lactulose (dosed to achieve several soft stools per day), lactose (similar effect to lactulose in some dogs), or low dose metronidazole (7.5 mg/kg PO BID) is routinely recommended before surgical intervention. While ameroid banding is lauded for its low immediate post-operative complications, some dog breeds (especially Yorkshire Terriers, Maltese) may develop portal hypertension when complete ligation is realized (days, weeks, months). Some surgeons now purposely place a larger size ameroid constrictor than indicated for complete ligation, on dogs intolerant to complete occlusion at surgery. Acquired PSS secondary to portal hypertension develops as early as 2 months in intolerant dogs that are totally ligated. Recent review of cellulose band ligation of extrahepatic PSVA documented this phenomenon. Clearly we still cannot predict which dogs will tolerate complete PSVA ligation and who should have surgery. There is no data even yet that the hepatic portal vasculature undergoes an adaptive accommodation to "forced" perfusion induced by PSVA ligation beyond the initial filling phenomonenon. Lastly, many clinicians remain naïve to the fact that asymptomatic PSVA have been recognized in dogs as old as 13 yrs!

Indications for PSVA Ligation: episodic neurobehavioral signs of HE, severe PU/Pd that restricts pet ownership, recurrent development of ammonium biurate crystalluria despite optimal medical management. Male dogs ligated to their tolerance that continue to develop ammonium biurate urolithiasis are given permanent urethrostomies.

Microvascular Dysplasia (MVD)

A congenital aberration of the hepatic microvasculature disturbing portal-sinusoidal perfusion and associated with attenuated tertiary portal branches, abnormal positioning of hepatic venules within portal triads, and an abnormal appearance or perfusion of hepatic venules. MVD occurs in kindreds with increased prevalence of PSVA where it appears to be a linked-inherited abnormality. In fact, dogs with MVD outnumber dogs with PSVA in certain terrier kindreds by 5:1 or more. MVD dogs typically DO NOT demonstrate routine hematologic, biochemical, or clinical changes consistent with PSVA although they have abnormal SBA concentrations that overlap. Most MVD dogs are discovered by routine screening for PSVA. However, MVD also may be serendipitously identified later in life when a SBA test is performed for the first time during an illness. Screening puppies from high risk breeds (SBA or UBA) is encouraged to eliminate such diagnostic confusion later in life. Most MVD dogs do not develop hyperammonemia or ammonium biurate crystalluria and most DO NOT require medical therapy or even a reduction in protein intake. In rare symptomatic cases, clinical signs are controlled with medical management as for PSVA. However, in the author's experience, most symptomatic MVD dogs have a PSVA and were erroneously labeled as MVD or have another liver syndrome. Some dogs with MVD develop a progressive veno-occlusive lesion.

Portal Hypoplasia vs Portal Hypoperfusion

Portal hypoplasia is used by some pathologists to describe attenuated intrahepatic portal vasculature. Unfortunately, this terminology implies a congenital abnormality. Any disorder that diminishes portal venous perfusion (e.g., portal venous thrombus, portal venous stenosis, surgical creation of an Eck fistula), imparts a similar histologic pattern (lobular atrophy, inconspicuous portal venules, lymphatic distention, and physiologic adaptation of the hepatic artery to increase blood flow). Arteries subjected to higher flow / pressure become tortuous causing an increase in their cross sectional profiles (arteriolization). Histologic features in dogs with surgically created PSS cannot be differentiated from dogs with PSVA, MVD or non-cirrhotic portal hypertension. The literal definition of portal hypoplasia is underdevelopment, incomplete or arrested development of the portal vein. Portal venous hypoperfusion, is a more appropriate descriptive term.

Portal Vein Atresia

Atresia indicates the congenital absence of a passageway. Portal atresia is diagnosed when the extrahepatic portal vein is judged to be very small or absent or when there is no tolerance to occlusion of a single PSVA. Eventually this abnormality is associated with multiple APSS and ascites. There is no treatment except medical management of HE and ascites. Without multisector CT imaging, these dogs are commonly operated with the expectation of finding a single PSVA.

Non-Cirrhotic Portal Hypertension (NCPH)

This syndrome is impossible to clearly distinguish from portal vein hypoplasia and constitutes an overlap syndrome that has confused retrospective case studies. At times, NCPH has been mislabeled as hepatoportal fibrosis. A curious disorder histologically indistinguishable from PSVA and MVD, NCPH involves diminished perfusion of the tertiary portal branches and is associated with portal hypertension, multiple APSS, and ascites (variably). Affected dogs range in age from 3 mths to 8 yrs (most < 4 yrs) at initial diagnosis. NCPH has been diagnosed in 12 Doberman Pinchers, 7 Cocker Spaniels, 5 Rottweilers, and multiple other breeds. It also has been documented in littermates (Dobermans, Cocker Spaniels, Standard Schnauzers). A several week history (or longer) of clinical illness precedes initial presentation. Historical features include: abdominal enlargement (ascites), gastrointestinal signs (vomiting, diarrhea), polydipsia, HE, and melena. Physical findings include: poor body condition and small stature. Common clinicopathologic features include: RBC microcytosis (60%), high serum ALP and ALT activities (3-5 fold, respectively, 60%), hypoalbuminemia (76%), low BUN (40%),low urine SG (69%). Abdominal effusion is a pure transudate. Abdominal US discloses microhepatica, abdominal effusion, and multiple APSS. Extrahepatic portal venous thrombi have been identified in some dogs. Hepatic parenchyma may appear hyper-, hypo, or heterogeneously echoic or normal. Liver function assessment by SBA is always abnormal. Dogs are inconsistently hyperammonemic and may not demonstrate ammonium biurate crystalluria. Diagnosis requires liver biopsy to rule out acquired necroinflammatory or fibrosing liver syndromes as an underlying cause of APSS. Liver biopsy by laparoscopy is recommended owing to the healing problems created by ascites. Treatment is symptomatic for HE and to control ascites (sodium restriction, diuretic therapy, usually combination of furosemide and spironolactone). Some dogs live a normal life span, some require lifelong medical management for HE and ascites, and some live well only on a prescription diet manufactured for dogs with hepatic insufficiency, and some have done well without treatment after initial medical management. Hypoalbuminemic dogs may have a concurrent intestinal lesion (e.g., inflammatory bowel disease). A severe bout of hemorrhagic gastroenteritis historically precedes development of NCPH in many dogs. This syndrome resembles a disorder in humans NCPH) associated with poor socioeconomic conditions (high incidence of enteric bacterial and parasitic infections). A similar lesion can be induced in rabbits and dogs by intraportal injection of killed nonpathogenic Escherichia coli. In man, individuals with NCPH have a better prognosis than individuals with APSS secondary to cirrhosis, similar to the situation in dogs. Affected people may live a relatively normal lifespan similar to some dogs with NCPH.

Hepatic Arteriovenous Fistula

An uncommon, usually congenital malformation. Arterialization of the portal circulation leads to portal hypertension, APSS, and abdominal effusion. Hepatic vascular abnormalities distant to the primary fistula are common. Despite fistula resection or occlusion, many dogs are not cured.