Liver manifestations of HHTQuazi Al-Tariq MD

Justin McWilliams MD

PURPOSEThis presentation is targeted to radiologists and interventional

radiologists who may be involved in diagnosis and treatment of Hereditary Hemorrhagic Telangiectasia (HHT) patients with liver involvement.

Topics to be discussed include: Basic pathophysiology of HHT, specifically typical shunt

mechanisms and their implications Multi-modality imaging findings, including CT, US,

angiography, and MRI Possible treatment options and the potential role of the

interventional radiologist

BACKGROUNDHereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-

Rendu Syndrome, is an autosomal dominant disorder which occurs with a reported frequency of about 1/7,000 persons

HHT is characterized by mucocutaneous and/or visceral angiodysplasias, which may range from telangiectasias to arteriovenous malformations

Liver involvement is common in HHT, particularly in patients with HHT type 2, with a reported prevalence of over 50% in some studies

BACKGROUNDHHT can be viewed as a spectrum ranging from

telangiectasias to AVMs Telangiectasias are focal dilatations of the

post-capillary venules, without preserved capillaries

AVMs are larger and represent direct arterial to venous communications

Both are associated with fibrous proliferation with preservation of the intervening parenchyma, which can give rise to pseudo-cirrhotic liver.

Telangiectasia

AVM

CLINICAL IMPORTANCEPatients with HHT liver involvement are at risk for development of

congestive heart failure, portal hypertension, cholangitis, and atypical cirrhosis

The predominant intra-hepatic shunt determines which outcome the patient is likely to have Arteriovenous shunting -> CHF Arterioportal shunting -> Portal hypertension

Therefore, imaging to identify shunt patterns may allow patients to be stratified based on their likelihood for certain outcomes

Imaging of patients with HHT and liver disease may be carried through multiple modalities, including CT, US, MRI, and angiography

CT

Multiphase (arterial, portal venous, and late venous) CT is the preferred CT imaging technique

Multi-planar reformations, 3D maximum intensity projections (MIPs), and 3D volume rendering may be helpful

A fourth “late arterial” or arteriolar phase, which is acquired after a short delay (5 seconds) following the “early” arterial phase may also be used Most authors feel that there is little value

added with the late arterial acquisition

CTArterioportal shunts are suggested when there is early and prolonged

enhancement of the portal vein during the arterial phase. Enhancement of the portal vein may approach that of the aorta.

Arteriovenous shunts are thought to be present when there is opacification of the hepatic veins during the arterial phase.

Portosystemic venous shunts are usually a microscopic phenomenon. However, a dilated portal vein communicating with a hepatic vein branch may sometimes be visualized on CT.

Arteriovenous shunting. Note enhancement of the hepatic veins (arrows) during arterial acquisition

CTIn addition to shunts, other findings may be evident with multiphase CT: Telangiectasias may be seen as rounded, arterially enhancing peripheral

lesions, usually with a diameter of less than 10 mm. Multiple telangiectasias may coalesce to give the appearance of what has been termed “confluent vascular masses”

Transient hepatic attenuation differences (THADs) are peripheral, often wedge shaped hyper-attenuating areas on arterial phase imaging which become iso-attenuating during the portal venous phase.

Arrow indicates multiple telangiectasias forming a confluent vascular mass

CTCT may demonstrate other findings particular to the predominant

shunting mechanism and thus the clinical subclassification:• In the portal hypertension group, findings of enlarged portal veins,

splenomegaly, ascites, and portosystemic collaterals may be seen

Multiphase CT in patient with arterioportal shunting demonstrates evidence of portal hypertension including portal vein enlargement and ascites.

CTCT may demonstrate other findings particular to the predominant

shunting mechanism and thus the clinical subclassification:• In the high output group, expected findings include cardiac dilatation,

enlarged hepatic veins, and pleural effusions

Multiphase CT in patient with arteriovenous shunting demonstrates evidence of high-output cardiac failure including cardiomegaly, enlarged hepatic veins, and ascites.

CTCT may demonstrate other findings particular to the predominant

shunting mechanism and thus the clinical subclassification:• In the biliary disease group, one may be able to see biliary strictures or

peribiliary cysts• This is the rarest subtype

A macronodular liver may be seen with any of the three subtypes

USUltrasound allows rapid evaluation of the liver in HHT without ionizing radiationCommon grey-scale findings include dilatation and tortuosity of the proper hepatic

artery and its branches, which may be seen as multiple tubular structures within the liver with echogenic walls

The size of the hepatic arteries is generally proportional to the amount of arteriovenous shunting

Other possible grey scale findings include hepatomegaly, splenomegaly, nodular liver surface contour, and dilated portal vein (>12 mm at its mid-portion)

Grayscale and color Doppler ultrasound images demonstrate dilated hepatic artery branches and aneurysm formation in a patient with large arteriovenous shunting.

US

Doppler techniques add important information about flow dynamics, which aids in the identification of the various shunts

•In cases of arterioportal shunts, one can see pulsatile hepatofugal flow within the portal system

Color and spectral Doppler ultrasound images demonstrate hepatofugal portal venous flow with pulsatility, reflecting arterialization from arterioportal shunts.

USArterial velocity is increased in affected HHT patients,

while portal and hepatic veins are not significantly different from healthy controls

• The arterial velocity is directly related to arterial size and likely the result of increased shunting

• This does not usually translate into increased venous velocity

– Instead of the multiphasic waveform which varies with the cardiac cycle, a continuous monophasic or biphasic waveform may be seen in the hepatic veins

– This may be due to variability in the size of the hepatic veins as well as decreased compliance of the liver secondary to increased arterial inflow

Spectral Doppler ultrasound image demonstrates continuous biphasic waveform in the left hepatic vein in this patient with large arteriovenous shunting

MRIThe role of MRI for the evaluation of the liver in HHT has significantly increased

over the last several years due to advancements in technology, including higher field strengths, phased array coils, and high performing gradients

The goals of MR in this clinical scenario are the same as those outlined for CT Establish shunt pattern, assess for perfusion abnormalities, identify pertinent

findings given the subcategory of disease Another potential advantage of this modality is the use of flow quantification

to elicit flow dynamics and ventricular function

MRIAlthough imaging protocols will vary, the following sequences are obtained

at the author’s institution Axial T1, single shot fast spin echo (SS-FSE), T2 single shot and FSE, and T2

spectral selection attenuated inversion recovery (SPAIR) Dynamic MRA may be obtained in a single breath hold using a T1

weighted 3D fast field echo and bolus tracking On a separate work station, the dynamic data sets may be used to

create multiplanar reconstructions, MIPs, and cine views

T2 image demonstrates regional perfusion abnormlaity

MRA demonstrates dilated tortuous MHA

ANGIOGRAPHYSelective angiography with digital subtraction is rarely needed for diagnosis,

but remains an alternate method to evaluate for liver involvement in patients with HHT

Celiac and hepatic angiography will demonstrate arteriovenous and arterioportal shunting as well as flow dynamics

High volume superior mesenteric arteriography can be used in order to visualize patency and flow direction of the portal system

Selective catheterization of the celiac axis in a patient with multiple arteriovenous shunts demonstrates a dilated, tortuous hepatic artery, and flow reversal of the gastroduodenal artery due to sump effect

ANGIOGRAPHYThe most commonly seen angiographic finding in patients with HHT is

multiple telangiectasias/AVMs along with hepatic artery dilatation In patients who are symptomatic, portovenous and arterioportal shunts

could be demonstrated However, in cases of combined shunt types, ie. Arteriovenous and

portovenous, there is often poor visualization of the portovenous shunt due to contrast dilution through the A-V shunts

TREATMENT

In the past, hepatic arterial embolization was used to treat mesenteric steal as well as large arteriovenous or arterioportal shunts However, many of these cases were complicated

by hepatic necrosis and death In arteriovenous shunts, embolization can

worsen ischemia of the peribiliary plexus and cause biliary ductal necrosis

In arterioportal shunts, embolization of both the arterial and portal venous supply can lead to widespread parenchymal necrosis

In the presence of portal to hepatic vein shunts, the hepatic artery becomes the primary nutrient supply to the liver, thus making arterial embolization even more unfavorable

Superselective coil embolization of several arterioportal shunts was performed in an attempt to ameliorate severe portal hypertension in this patient with HHT. The patient suffered transaminitis and abdominal pain, but no noticeable improvement in portal hypertension ensued. Hepatic arterial embolization in HHT patients should be undertaken only in very rare circumstances.

TREATMENTThe vast majority of HHT patients with liver involvement have relatively minor liver AVMs

and will never be symptomaticIn <5% of HHT patients, severe liver AVMs will result in clinical complications such as those

described on previous slidesMedical management is first-line for liver-related complications in HHT patients High output cardiac failure can usually be managed by correcting anemia and diuretic

therapy, with or without anti-arrhythmics and beta blockade Portal hypertension is managed in the same manner as in cirrhotic patients, with volume

restriction and diuretics for ascites, and beta-blockade and endoscopic banding for varices.

TREATMENT

Some patients, particularly those with high-output cardiac failure from large arteriovenous shunts, may be difficult to manage with conventional medical therapies

Vascular endothelial growth factor (VEGF) appears to be upregulated in patients with HHT, making anti-VEGF therapy with bevacizumab (Avastin) a back-up treatment option Published results using a regimen of 6 infusions of Avastin (5mg/kg)

over a 12 week period are very promising Case reports demonstrated reversal of cholestasis, cardiac failure, and ascites.

Treatment also resulted in decreased liver vascularity and volume.

Mitchell A, Adams LA, MacQuillan G, Tibballs J, vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasiaLiver Transpl. 2008 Feb;14(2):210-3.

Genentech 2012

TREATMENTWhile multiple medical options exist, the definitive treatment for

symptomatic liver involvement in HHT is transplantation. 1-, 5- and 10-year patient and graft survival are excellent (82.5%)

When a patient should be listed for transplant is debatable, but it is generally considered for:

Intractable heart failure Severe biliary disease complicated by recurrent episodes of cholangitis Widespread biliary necrosisIt has recently been recommended that an additional MELD score of 40

and 22 points, respectively, should be assigned to HHT patients with acute biliary necrosis or intractable heart failure waiting for transplant.

Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000; 343: 931–6.

SUMMARYAfter reviewing this presentation, the viewer should have a

clearer understanding of the liver manifestations of HHT. A multi-modal approach can be taken by the radiologist

including CT, US, MRI, and angiography The clinical features typically reflect the pervasive intra-

hepatic shunt type Treatment is tailored to the clinical symptoms. Complications

of embolization therapy have limited its role in favor of medical management and transplantation.

REFERENCESStabile Ianora, AA, Memeo, M, et al. Hereditary hemorrhagic telangiectasia: multi-detector

row helical CT assessment of hepatic involvement. Radiology 2004; 230: 250-259.Garcia-Tsao G, Korzenik JR, et al. Liver disease in patients with HHT. N Eng J Med 2000; 343:

931-936.Naganuma H, Ishida H, Niizawa M, Igarashi K, Shioya T, Masamune O. Hepatic involvement

in Osler-Weber-Rendu disease: findings on pulsed and color Doppler sonography. AJR1995 ;165:1421 -1425

Saluja S, White, RI. Hereditary hemorrhagic telangiectasia of the liver: hyperperfusion with relative ischemia-poverty amidst plenty. Radiology 2004; 230: 25-27.

Wu JS, Saluja S, et al. Liver involvement in hereditary hemorrhagic telangiectasia: CT and clinical findings do not correlate in symptomatic patients. AJR 2012; 187: 399-405.

Caselitz M, Bahr MJ, et al. Sonographic criteria for the diagnosis of hepatic involvement in HHT. Hepatology 2003, 37: 1139-1146.

Whiting JH, Korzenik, JR, et al. Fatal outcome after embolotherapy for hepatic arteriovenous malformations of liver in two patients with HHT. JVIR 2000; 11: 855-858.

CT– A macro-nodular liver may be seen in all

of the above A

B C

A- cardiomegaly B- peribiliary cyst (arrow) C-macro-nodular liver