Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

Section VIII HEPATOLOGY

CHAPTER 55. Hepatic Vascular Disorders

Kunal Gupta, MD, MBA and Nicholas Ferrentino, MD

Image What is the average total blood flow to the liver in mL/min?

Blood flow normally ranges between 800 and 1200 mL/min. The portal vein supplies the majority of the blood (approximately two-thirds) with the hepatic artery supplying the remainder.

Image What is the approximate amount of oxygen that the liver is able to extract from the blood and how does this compare to most other gastrointestinal organs?

The liver is relatively unique in its ability to extract oxygen from the blood—up to 95%—making it much more efficient than most gastrointestinal organs.

Image What is the proposed mechanism of ischemic reperfusion injury?

Formation of oxygen-free radicals, predominately by the enzymes NADPH oxidase and xanthine oxidase.

Image True/False: Ischemic liver diseases are more common in the elderly.

True. While ischemic liver disease may occur at any age, it most commonly occurs in the older population. This age group is more susceptible to severe cardiac and pulmonary diseases that predispose to ischemia.

Image What are some causes of ischemic hepatitis?

Any cause of shock, hemodynamic instability, or “low flow” state (such as with congestive heart failure [CHF]) can cause ischemic injury to the liver. Ischemia can also be caused by local disruption of the hepatic blood flow such as in hepatic sickle cell crisis and hepatic artery thrombosis.

Image What are the common symptoms of ischemic hepatitis?

Ischemic hepatitis is usually detected because of extreme elevations in liver biochemical tests (aminotransferase levels, particularly) following a hypotensive episode. Occasional patients have symptoms suggesting acute hepatitis including nausea, vomiting, anorexia, malaise, and right upper quadrant (RUQ) pain.

Image What is the classic pattern of liver biochemical tests of ischemic hepatitis?

The typical pattern consists of a stark rise in serum aminotransferase levels also associated with a large rise in lactate dehydrogenase levels. Peak aminotransferase levels are typically 25–250 times the upper limit of normal and are reached within 1 to 3 days of the hemodynamic insult. Following recovery from the hypotensive episode, the liver tests rapidly return to normal.

Image What is the hallmark histopathologic finding in ischemic disorders of the liver?

Necrosis of hepatocytes in zone 3 of the hepatic acinus associated with a variable degree of architectural collapse around the central vein.

Image How does hepatic veno-occlusive disease typically present clinically?

Nonthrombotic, fibrous, obliterative endophlebitis of small intrahepatic veins, originally described by Chiari, is now referred to as hepatic veno-occlusive disease. Hepatic veno-occlusive disease typically presents with hepatomegaly, ascites, and weight gain.

Image Name the classic etiology of hepatic veno-occlusive disease.

Pyrrolizidine alkaloid ingestion typically from plants used to make some herbal teas. Other etiologies include irradiation and high-dose chemotherapy prior to bone marrow transplantation, systemic lupus erythematosus, and agents such as azathioprine, cytosine arabinoside, 6-mercaptopurine, urethane, and possibly oral contraceptives.

Image What is the mainstay of treatment for hepatic veno-occlusive disease secondary to pyrrolizidine alkaloid ingestion?

One-half of patients recover completely with fluid and sodium restriction.

Image True/False: Serum aminotransferases are typically elevated in hepatic veno-occlusive disease.

True (80%–85%). Hyperbilirubinemia (bilirubin 15–20 mg/dL) and elevated alkaline phosphatase (250–300 IU/L) may also occur.

Image What percentage of bone marrow transplant patients are thought to acquire hepatic veno-occlusive disease?

10%–20%.

Image What is the reported mortality rate from hepatic veno-occlusive disease in bone marrow transplant patients?

20%–40%.

Image What is the classic order of manifestation of signs and symptoms in hepatic veno-occlusive disease in the bone marrow transplant setting?

Weight gain occurring 8 or 9 days following the transplant, hyperbilirubinemia in 11–12 days, elevated aspartate aminotransferase and alkaline phosphatase in 13–15 days, and hepatomegaly and ascites within 1–2 weeks of bone marrow transplantation.

Image How is the diagnosis of hepatic veno-occlusive disease made?

If the patient is status post bone marrow transplant and the clinical syndrome typical, presumptive diagnosis can be made without further studies. In less clear cases, liver biopsy is warranted. Unfortunately, these patients are usually severely thrombocytopenic complicating the performance of any invasive procedure. The transjugular approach to liver biopsy may be a less risky alternative in this situation. Ultrasound with Doppler flow study, CT scan, and MRI are all options to determine hepatic vein patency to rule out Budd–Chiari syndrome.

Image What are the characteristics of liver biopsy that suggest hepatic veno-occlusive disease?

The hepatic venule is typically obliterated, hepatocyte dropout is noted, and sinusoidal dilation is present.

Image What etiology of hepatic veno-occlusive disease is associated with a higher incidence of severe, chronic, and often fatal disease progression?

Bone marrow (peripheral stem cell) transplantation.

Image What disease is associated with “atrophic infarcts of Zahn”?

Nodular regenerative hyperplasia.

Image Name three processes associated with peliosis hepatis.

Tuberculosis, AIDS, and drugs.

Image How many major hepatic veins drain into the inferior vena cava?

Three.

Image What are the causes of Budd–Chiari syndrome?

Hypercoagulable states and neoplasms are common causes in the Western world. Examples include myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, antithrombin III deficiency, protein C and S deficiencies, neoplasms, infections, collagen vascular diseases, Behcet’s disease, sarcoidosis, oral contraceptives, pregnancy, inflammatory bowel disease, cirrhosis, polycystic liver disease, and idiopathic. Membranes or webs are important causes of outflow obstruction in Asia and South Africa.

Image Name neoplasms associated with Budd–Chiari syndrome.

Primary hepatocellular, renal, adrenal, pulmonary, pancreatic, and gastric carcinomas. Benign and malignant vascular neoplasms (leiomyomas, leiomyosarcomas, and rhabdomyosarcomas) arising within the hepatic veins or vena cava have also been associated with Budd–Chiari syndrome and hepatic failure.

Image What is the typical clinical presentation in Budd–Chiari syndrome?

A spectrum of disease is possible, ranging from an asymptomatic state to fulminant hepatic failure or cirrhosis with associated complications. Acute obstruction is associated with RUQ pain, nausea and vomiting, hepatomegaly, and ascites. Jaundice and splenomegaly may be noted but are usually mild.

Most patients present with a subacute course of less than 6 months and complain of vague RUQ discomfort, hepatomegaly, mild-to-moderate ascites, and splenomegaly. Jaundice is either absent or mild. Symptomatic disease of more than 6 months presenting as fatigue, bleeding varices, encephalopathy, coagulopathy, hepatorenal syndrome, and/or malnutrition suggests chronic obstruction. Massive hepatocellular necrosis with fulminant hepatic failure is a rare manifestation of Budd–Chiari syndrome and typically follows rapid and complete occlusion of all hepatic veins. Progressive encephalopathy, coagulopathy, and death are inevitable within 8 weeks of occlusion if treatment is not provided.

Image What three symptoms characterize acute, rapidly progressive Budd–Chiari syndrome?

Hepatomegaly, RUQ pain, and ascites.

Image An enlarged spleen is often found in patients with Budd–Chiari syndrome. Name two possible causes of an enlarged spleen in this disorder.

Portal hypertension and an underlying myeloproliferative disorder.

Image What is the prognosis for symptomatic, untreated patients with Budd–Chiari syndrome?

Poor. The average life span is from 3 months to 3 years after initial diagnosis. The patients often develop renal failure, variceal bleeding, hepatic encephalopathy, and jaundice.

Image What is the prognosis for asymptomatic individuals with Budd–Chiari syndrome?

Excellent. This suggests thrombosis of only two of the three hepatic veins or adequate collateral compensation.

Image Patients often do not present acutely with Budd–Chiari syndrome. If an obstruction is established in this case, what is the treatment of choice?

Surgical decompression of the liver via shunt surgery. In those with advanced fibrosis or cirrhosis, liver transplantation may be considered.

Image Describe the histological appearance of the liver in Budd–Chiari syndrome.

Acute obstruction reveals significant centrilobular congestion and dilation of sinusoids. Atrophy, necrosis, and dropout of centrizonal hepatocytes with extension to periportal regions are present with severe injury. With chronic disease, complete obliteration of central veins associated with midzonal and centrilobular fibrosis with or without cirrhosis is noted.

Image What laboratory abnormalities are usually present in Budd–Chiari syndrome?

Standard laboratory investigations are rarely helpful. Twenty-five percent to 50% of patients with venous outflow obstruction present with either normal or mildly abnormal aspartate and alanine aminotransferases. However, patients presenting with acute disease or fulminant hepatic failure may display values greater than 1000 IU/L, especially if there is accompanying portal vein thrombosis. In addition, serum bilirubin, alkaline phosphatase, and prothrombin time are usually normal or mildly elevated.

Image What tests are helpful in the diagnosis of Budd–Chiari syndrome?

Radiologic imaging and liver biopsy.

Image What is the sensitivity of ultrasound in the evaluation of Budd–Chiari syndrome?

85%–95%. The addition of Doppler to conventional ultrasound is more sensitive than real-time investigation alone.

Image What is the role of the CT scan in the evaluation of Budd–Chiari syndrome?

The CT scan is helpful in evaluating abnormalities of the hepatic veins and vena cava including membranes, the extent of hepatic parenchymal disease, and the presence of ascites and splenomegaly.

Image What is the gold standard in the diagnosis of Budd–Chiari syndrome?

Angiography. It not only provides information regarding cause and location of obstruction but is also helpful in obtaining pressure measurements, which are important for surgeons before decompression. Ideally, all patients considered for surgery should undergo angiography in addition to liver biopsy.

Image What medical options exist for the treatment of Budd–Chiari syndrome?

Medical therapies, while generally ineffective, include sodium restriction, diuretics, and therapeutic paracentesis. In patients who present with acute incomplete thrombotic obstruction, anticoagulation, and thrombolysis are alternatives.

Image Discuss the role of interventional radiology in the treatment of Budd–Chiari syndrome.

Percutaneous transluminal balloon angioplasty and stent placement is an effective therapy for hepatic outflow obstruction secondary to caval webs or hepatic venous stenosis. Often when angioplasty and stenting is ineffective, the transjugular intrahepatic portosystemic shunt (TIPS) can also be used to decompress congested segments in the liver by creation of an alternative venous outflow tract.

Image What surgical shunts are useful in the treatment of Budd–Chiari syndrome?

Decompressive shunts should be considered the standard of care for patients with acute or subacute venous occlusion. Options include 1) side-to-side portocaval shunts, 2) mesocaval shunts (for patients with compression of the retrohepatic cava by caudate lobar hypertrophy), and 3) mesoatrial shunts (for patients with caval obstruction and a significant gradient between the cava and right atrium). After surgery, long-term anticoagulation is recommended to minimize the chance of recurrent thrombosis.

Image When should liver transplantation be considered in patients with Budd–Chiari syndrome?

• Fulminant liver failure

• End-stage liver disease

• Patients with significant liver disease who decompensate after receiving decompressive shunts

• Shunt failure

• Venous thrombosis attributable to protein C, protein S, or antithrombin III deficiency

Image What is the leading cause of portal hypertension?

Thirty percent of the cases of portal hypertension in children and 75% of the cases in adults are caused by portal vein thrombosis.

Image What are the “local” risk factors for portal vein thrombosis?

Cancer, focal inflammatory lesions, injury to the portal venous system, and cirrhosis.

Image What three Philadelphia-negative myeloproliferative diseases are considered “general” risk factors for portal vein thrombosis?

Polycythemia rubra vera, essential thrombocythemia, and myelofibrosis.

Image What is the difference between acute and chronic portal vein thrombosis?

Acute portal vein thrombosis is the sudden formation of a partial or complete thrombus in the portal vein, whereas chronic portal vein thrombosis (also known as portal cavernoma) is a thrombus in the portal vein, which involves the formation of hepatopetal collateral veins.

• • • SUGGESTED READINGS • • •

Plessier A, Valla DC. Budd–Chiari syndrome. Semin Liver Dis. 2008;28(3):259-269.

Crawford JM. Vascular disorders of the liver. Clin Liver Dis. 2010;14(4):635-650.

Senzolo M, Riggio O, Primignani M; Italian Association for the Study of the Liver. Vascular disorders of the liver: recommendations from the Italian Association for the Study of the Liver (AISF) ad hoc committee. Dig Liver Dis. 2011;43(7):503-514.