Congenital and Acquired Disorders of Liver Perfusion: Backgrounds, Risk Factors and Treatment Options
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
Especially in dogs disorders of liver perfusion are an important group. Many of these disorders are congenital. Examples are congenital portosystemic shunts, which are an inherited disease in many different dog breeds, primary portal vein hypoplasia, and arteriovenous fistula. There are also acquired disorders of the portal liver perfusion, usually due to chronic portal hypertension. The most common cause is chronic hepatitis with fibrosis or cirrhosis, but portal vein thrombosis may also cause portal hypertension leading to acquired portosystemic shunting.
All forms of portosystemic shunting lead to neurological symptoms of hepatic encephalopathy. This is most easily and specifically diagnosed by measuring fasting blood ammonia or by performing a rectal ammonia tolerance test.
Most liver perfusion disorders can be readily treated, but a good diagnosis is a prerequisite to define the best approach.
Hepatic encephalopathy (HE) is defined as dysfunction of the brain secondary to liver dysfunction. HE occurs as a frequent syndrome in dogs and cats. HE is only a complex of symptoms caused by liver diseases. In all species chronic HE is caused by shunting of portal blood past the liver: portosystemic collateral circulation, which may be acquired due to portal hypertension or congenital in case of a single inherited type of shunt. Chronic HE is therefore often called portosystemic encephalopathy. The great reserve capacity of the liver protects animals against HE, even in severe liver disease other than fulminant hepatitis. The presence of even severe portosystemic shunting alone is not sufficient to develop HE in most cases; it only causes HE when present in combination with compromised liver function. This is of course the case in liver diseases such as chronic hepatitis leading to portal hypertension and acquired portosystemic collaterals. However, also in dogs and cats with congenital shunts the liver function becomes increasingly inadequate. Normally the liver grows due to expression of growth factors of which the expression needs stimulation by factors from the portal circulation. Therefore, without this stimulation the liver of animals with congenital shunts lacks normal growth so that with growth of the body the liver stays more and more behind. This explains why animals with congenital liver shunts usually develop symptoms only when six months old or older.
Very characteristic is the episodic nature of HE, with fluctuations between grade one and the more advanced stages in the same animal. Usually one or few days of severe signs of HE alternate with more or less normal periods of one or several weeks. Apart from the neurological symptoms of HE, non-neurological signs related to the underlying disease may be seen. Symptoms associated with the chronic liver diseases causing portosystemic encephalopathy are polyuria, vomiting, diarrhoea, weight loss, decreased endurance, inactivity, and in case of congenital diseases sometimes retarded or insufficient growth.
Neurological signs almost never include epileptic attacks. Epilepsy alone without any of the other signs (described in the list below) is never due to HE.
Neurological symptoms seen in dogs and cats with hepatic encephalopathy:
Stage 1: Apathy, decreased mental alertness, "staring" glance, unawareness of surroundings
Stage 2: Ataxia, circling, head pressing against obstacles, blindness, salivation
Stage 3: Stupor, severe salivation, completely inactive but can be aroused
Stage 4: Coma, total irresponsiveness
Non-neurological signs associated with liver diseases causing hepatic encephalopathy:
All stages: Polyuria/polydipsia, vomiting, decreased endurance, inactivity, sometimes insufficient growth in dogs with congenital shunts
General: Periodic occurrence is very typical
Ammonia measurement in plasma is the only practical way to diagnose HE. Due to the incorporation of ammonia into glutamine in many tissues the arterial ammonia concentration may be higher than that in venous blood. Moderate hyperammonaemia may be missed in venous samples. In case of doubt an ammonia tolerance test always gives a clear result. This test is also very reliable in diagnosing portosystemic collateral circulation in cases not (yet) having HE. The test is performed by giving a 5% ammonium chloride solution deep rectally (10–20 cm). Ammonia is quickly absorbed into the portal blood and should be nearly completely metabolised by the liver (even in case of liver disease) during the first passage. Only in case of portosystemic shunting ammonia does (in part) not reach the liver and peaks in peripheral plasma. The best sampling times are before and 20 and 40 min after administration. A distinct increase to above 100 and usually 150 μmol/L is seen in case of shunting (normal levels are below 45 μmol/L). The extra ammonia load given with this test is never aggravating the encephalopathy, there is no risk involved in application of it. In some 40% of dogs with HE ammonium biurate crystals may be detectable in the urine sediment. If present, this is a highly specific indication for conditions causing HE in non-Dalmatian dogs.
Congenital Portosystemic Shunts (PSS)
These are congenital abnormal vessels connecting the portal vein and a large vein outside the splanchnic venous system, usually the vena cava or the vena azygos. PSS have been proven inherited in small dog breeds with extrahepatic shunts and in large breeds with intrahepatic shunts and they are presumably inherited in all breeds. Shunts occur in both dogs and cats. PSS are large-diameter vessels so that there is a preferential flow of portal blood through the shunt bypassing the liver.
Portosystemic shunts are localised intrahepatic or extrahepatic. The intrahepatic shunts usually originate from the left main branch of the portal vein (persistent ductus venosus) but in some cases they come from the right branch. The left sided shunts are more superficial and easier to operate than the right sided shunts, which lie deeper and are often also wider and shorter. Intrahepatic shunts occur in large dog breeds. Extrahepatic portocaval shunts are seen in toy or middle size breeds, and may originate from the gastroduodenal vein, the gastrosplenic vein or the mesenteric vein. Most extrahepatic shunts in dogs end in the vena cava just cranial to the right kidney. There are also extrahepatic shunts terminating in the vena azygos or hemiazygos. Because of the vena azygos is much smaller than the vena cava, the flow through porta-azygos shunts is much less and these dogs usually have less severe signs, often becoming apparent at a later age. It is not unusual to see a dog with a porta-azygos for the first time at an age of 5–7 years. In rare cases the portal vein is only connected with another systemic vein, without a normal continuation to the liver cranial to the branch of the shunting vessel. The symptoms are in all cases the same. Shunts occur in many different dog breeds. Cairns and Yorkshire terriers, Malthesian dogs, dachshunds, Labrador retrievers, Bernese mountain dogs, Hovawarts, and Irish wolfhounds are frequently affected. In a number of breeds the incidence measured was between 1–5% of the dogs born, and such figures apply presumably to all of the above mentioned breeds. In addition, shunts occur less frequently in many other breeds. Congenital shunts in cats are usually extrahepatic, but there are also intrahepatic shunts. In cats there is a wide variety of locations; shunts may be located in between the liver and the diaphragm, but may also be located as far back as the pelvic entrance. Shunts affect both females and males.
In almost all cases there is apathy, excessive sleeping, and rapid fatigue. The animal may or may not be underweight; stunted growth is rarely seen. Polydipsia occurs in many cases (> 50%), as well as occasional vomiting, and variable appetite. Usually there are neurologic abnormalities varying from slight apathy (HE stage 1) to ataxia, pacing, periodic blindness, salivation (stage 2), stupor in combination with the stage 2 symptoms (stage 3) to even coma (stage 4). Epileptic attacks may occasionally occur but are never the only symptom of HE. Very characteristic is that the symptoms are periodic: days with more or less pronounced symptoms are followed by gradual improvement and a better or even normal period lasting usually for one or several weeks. Even coma is usually followed by spontaneous temporary improvement. The neurological symptoms of hepatic encephalopathy are explained in detail in the section about HE. There may be acute micturition problems in males caused by urethra obstruction by ammonium urate crystals. Although symptoms usually develop around half a year of age, patients may develop distinct neurological after several years; occasionally at old age (10 years).
The typical history with periodic symptoms. Physical examination reveals no specific findings. Ammonia measurement is the first step to confirm the diagnosis; the concentration is highly elevated in most cases. In case of doubt ammonia tolerance test results are always abnormal. Bile acids are increased in most cases, but they are less sensitive parameter than ammonia, and very non-specific. Bile acids are not only increased due to portosystemic shunting but also in case of cholestasis, and therefore in all liver diseases. The same applies to measurement of post-prandial bile acids, which are increase in many different liver diseases. Ammonia is only increased in case of shunting, and very rarely in dogs with an inborn error of a urea cycle enzyme. With the availability of a good table top analyser (blood ammonia checker, Menarini) Moderate degree anaemia and leucocytosis are frequent findings in animals with shunts, but these findings are usual in many diseases of the liver and of other systems and hence not specific. Abnormal ammonia values do not discriminate single congenital from multiple acquired shunts. Ultrasonography may directly visualize the shunt and it is advisable to find the localisation of the shunt before surgery. If ultrasonography is not conclusive, the shunt may be demonstrated by per rectal scintigraphy with 99mtechnetium. Contrast angiography by catheterization of the portal vein or the hepatic artery is invasive and obsolete. Histological examination of a liver biopsy reveals changes which are not specific (see under portal vein hypoplasia). Liver enzymes in plasma and albumin may or may not be in the abnormal range, but if abnormal the changes are mild. Radiographs or ultrasonography reveals small liver and large kidneys. Patients with portosystemic shunts never develop icterus.
Surgical closure of the shunt is the only specific treatment. The shunt is closed partially, permitting some portal blood to bypass the liver so that the portal pressure does not increase too much. There are three techniques to reach this: a ligature around the shunt, cellophane banding, and the ameroid constrictor. With all these techniques the shunt is closed partially and it closes completely over time. In experience hands the outcomes are similar with the three methods. Shunt surgery requires experience. After partial closure of the shunt more portal blood reaches the liver, so that production of local growth factors commences followed by rapid liver growth (in 1–2 weeks). This in turn results in less resistance to portal flow in the liver and further improvement of liver perfusion and growth. After two to three weeks the flow through the partially ligated shunt becomes so low that it closes spontaneously by a local blood clot which becomes organised. Complete normalisation of the liver is achieved in 70% of the cases with extrahepatic shunts, and in about 50% of the animals with intrahepatic shunts. It is very important to have the patient in an optimal condition before surgery; the chance of intra-operative or early post-operative complications is much lower with proper preparation. Supportive measures for encephalopathy including those for anaesthesia have been explained in that section. It is important to evaluate blood glucose before, during and after surgery, since these animals may develop hypoglycaemia due to poor liver function. Coagulation should also be checked before surgery and if necessary be corrected by blood or plasma transfusion. The surgical results in cats are poorer than those in dogs. A considerable fraction of dogs with shunts (about 10–15%) also has primary portal vein hypoplasia. These dogs have only partial improvement of liver blood flow, reduced liver growth, and permanent portal hypertension following surgery. The partially closed shunt remains patent and in severe cases there may be development of acquired portosystemic collaterals. Such dogs have partial improvement depending on the severity of the portal vein hypoplasia. These collaterals usually develop between 4–8 weeks after surgery. Such cases may show initial (partial) improvement after surgery, 1–3 months later followed by recurrence of hepatic encephalopathy. Even with this complication, such dogs are usually better off with than without surgery. Complete recovery usually occurs within a 3–4 weeks. Even severe neurologic signs are completely reversible. The prognosis of surgical intervention depends on the type of shunt. Without surgery, supportive care is insufficient to maintain normal life permanently. The mode of inheritance is not yet known and to date it is not possible to advise a breeding selection to eliminate the disease.
Liver congestion is usually caused by congestive heart disease such as atrial fibrillation and pericardial overfilling. An obstruction of the thoracic part of the caudal vena cava by tumour or thrombus can also cause hepatic congestion. Ascites caused by hepatic congestion is always haemorrhagic, because erythrocytes also escape from the congested capillary bed. Ascites due to primary liver disease is usually clear and colourless.
The hepatic congestion has no important functional consequences for the liver. Liver enzymes, bile acids or albumin in blood are usually not or only mildly abnormal.
The symptoms are those of the primary disease. As liver functions remain largely normal there are no typical signs of liver disease.
Usually conform diagnostic procedure of the heart.
Primary Portal Vein Hypoplasia
Synonyms are microvascular dysplasia and congenital hepatic fibrosis.
There has been much confusion in the literature; this disease has been given different names. The WSAVA consensus name is primary portal vein hypoplasia. Microvascular dysplasia was a re-invention of this already existing disease. This disease is characterized by a reduced development of the intrahepatic final branches of the portal vein. Consequently, portal blood does not reach the hepatocytes. This disease may vary from slight reduction in number of final portal branches to complete absence. There are many mild non-symptomatic cases which become only apparent when blood examination is done and reveals increased bile acids. Severe cases have ascites and acquired portosystemic collaterals. This may cause hepatic encephalopathy. The more severe cases are always seen at young age within the first year of life. Mild or subclinical cases may be detected at any age.
Histologically there is either hypoplasia of the branches of the portal veins, which are very small or invisible in all or part of the portal areas. There may be a variable amount of portal fibrosis. In response to reduced portal liver perfusion there is proliferation of the arterioles in the portal areas.
Underweight, ascites, often hepatic encephalopathy, polydipsia, occasionally vomiting. These symptoms may be present in more severe cases, and may be mild or absent in less severe or subclinical cases.
The diagnosis is always based on the combined interpretation of histology and ultrasonography. With echo-Doppler most dogs with portal vein hypoplasia have a hepatofugal flow (from the liver back to the caudal portal vein, and then via the collaterals to the vena cava) in the portal vein. This does not occur in congenital shunts. Another difference is that the kidneys are nearly always enlarged in dogs with congenital shunts, but not in other portal vein diseases. An experienced ultasonographer can visualise the differential diagnostic diseases: congenital shunt, portal vein thrombosis, and arteriovenous fistula. Ascites may be present in dogs with portal vein hypoplasia (colourless), arteriovenous fistula (colourless), and portal vein thrombosis (haemorrhagic) but not in dogs with congenital shunts.
Recovery is not possible. Only symptomatic treatment can be given to reduce HE (diet, lactulose), and ascites can be treated with potassium-sparing diuretics. Severe cases with ascites and sever HE should be euthanised.
Portal Vein Thrombosis
Thrombosis of the portal vein is a rare disease, seen with hypercoagulability of the blood such as occurs in the nephrotic syndrome, or in case of abnormal intima of the portal vein. It is in some cases associated with pancreatitis or with chronic exposure to corticosteroids (endogenous or exogenous). The histological picture is usually undistinguishable from that seen in congenital shunts, primary portal vein hypoplasia, and arteriovenous fistula. The haemorrhagic type of ascitic fluid is discriminatory. Chronic cases with acquired portosystemic collaterals may have HE.
In many cases haemorrhagic ascites. In chronic cases there may be signs of HE. In the acute phase there is general malaise and apathy, often nausea and vomiting.
The diagnosis is made by ultrasonography, by which the thrombus may be visualised. Doppler examination reveals a reduced portal flow, which may in chronic cases be hepatofugal. One sided thrombosis in a main branch is accompanied by an asymmetric liver.
Therapy depends on the primary disorder (e.g., nephrotic syndrome). Acute thrombosis may be relieved surgically. Platelet inactivation by aspirin (2dd 5 mg/kg) has been advised, but the beneficial effect has not been documented. One sided thrombosis in a main branch usually recovers spontaneously when the perfused side of the liver grows in compensation so that normal liver functions are restored. In chronic cases with (tendency of) hepatic encephalopathy symptomatic support to relief the encephalopathy may be required.
Shunts between the hepatic artery and the portal venous system give an abnormally high arterial pressure in the portal system, hence portal hypertension. These fistulas are very uncommon congenital disorders. The fistula is usually located in a liver lobe and consists of multiple tortuous, pulsatile vessels which may be recognised with ultrasonography. Dogs with this disease also have portal vein hypoplasia. This causes a reserved prognosis for surgical correction by hepatic lobectomy, which in itself may is sufficient to remove the fistula. Portal hypertension leads to formation of multiple portosystemic collaterals and ascites. Intrahepatic fistulas cause a reversal of the blood flow in the portal system known as hepatofugal (away from the liver, instead of hepatopedal) flow. This is characteristic with Doppler ultrasonography, but is also seen with primary portal vein hypoplasia and in some cases with portal vein thrombosis.
In all cases the resultant symptoms are those of portal hypertension: hepatic encephalopathy, ascites, depression, anorexia and vomiting.
Laboratory examination gives increased bile acids, and usually also increased ammonia due to portosystemic collateral circulation. Ultrasonography reveals the wide tortuous pulsatile vessels. Management
Surgical removal of the affected liver lobe or the extrahepatic fistula has been found helpful, but in due to congenital portal vein hypoplasia there is only partial improvement and these dogs need permanent support with low protein diet and lactulose. With this support the animal may be maintained well for many years.