BEVACIZUMAB USE IN A PATIENT WITH HEREDITARY HEMORRHAGIC

TELANGIECTASIA COMPLICATED WITH PULMONARY HYPERTENSION AND

SEVERE LIVER INVOLVEMENT

High-output heart failure; etiology and different treatment strategies

Introduction

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder

mainly affects skin, mucocutaneous tissue, lung, liver, brain and cardiovascular system(1-3).
It characterized with telangiectasias of the lips, face, oral cavity, fingers, trunk and
arteriovenous malformations (AVMs) were seen in visseral organs and mucocutaneous
tissues(1-3). Clinical presentation includes recurrent epistaxis, iron deficiency anemia due to
gastrointestinal blood loss, intracranial hemorrhage due to cerebral AVMs and dyspne,
hemoptysis, fluid retention, ascites and variceal bleeding regarding to cardiovascular and
hepatic involvement(2-5). Diagnosis is based on Curaçao criterias which composed of i)
Spontaneous, recurrent epistaxis ii) Telangiectasias at characteristic sites (Mucocutaneous,
face, lips, fingers, nose) iii) Visseral AVMs (Pulmonary, hepatic, cerebral, spinal,
gastrointestinal) iv) A first degree relative with HHT(6). Three of four criterias provide a
definitive diagnosis of HHT, whereas two of four criterias are considered as possible HHT(6).

Hepatic AVMs are seen in up to %75 of patients with HHT, most of them are
asymptomatic(4, 7). Hepatic AVMs can lead to mortal complications as congestive cirrhosis,
portal hypertension, pulmonary hypertension and high output cardiac failure (HOCF)(4, 7).
Although liver transplantation is considered the mainstay treatment of HHT related congestive
cirrhosis and HOCF, in some studies a VEGF inhibitor, bevacizumab was found to have
beneficial effects in reversing high output state and reducing epistaxis frequency(1, 8-10).

We reported a patient with HHT related HOCF and liver involvement who received
bevacizumab treatment.

Case Report

A 51-year-old female without any history of chronic disease was referred to our cardiology
clinic for further evaluation of increased pulmonary pressure on echocardiography. Over the
past 2 years, she had developed progressive dyspnea (WHO funtional capacity-III) and
associated palpitation and chest discomfort with exertion. Physical examination demostrated
the following; purple coloured papules on lips and neck (figure 1); heart rate 110 beats/min;
distended juguler veins; increased intensity of S2 heart sound; hepatomegaly; a continous
murmur on the epigastric area; mild edema; no clubbing or cyanosis. She had never smoked
or drank alcohol. Blood tests indicated mild iron deficiency anemia and elevated proBNP
levels ( pg/ml). Renal, hepatic, thyroid functions and viral serology were normal. ECG
showed sinus tachycardia. Transthoracic echocardiography (TTE) revealed preserved left and
right ventricle functions, enlarged right ventricle and increased right ventricular systolic
pressure (RVSP) of 45 mmHg. Only mild mitral and tricuspid regurgitation was appreciated.
V/Q lung scan was normal.

She stated that she and her sister had experienced epistaxis intermittently Left and right
ventricular systolic functions were normal in the echocardiogram. The right ventricle was
enlarged (44mm). PASP calculated from the velocity of tricuspid regurgitation was measured
as 45mmHg (TYV:3.2m/sec). No obstructive or restrictive pattern was found in the
spirometry test. There was no finding in favor of pulmonary embolism in the V/Q
scintigraphy. In the 6-minute walking test, the patient walked 480 meters and no desaturation
was observed. Pulmonary artery diameter (30mm) and right main pulmonary artery diameter
(25mm) were increased in thorax CT. Due to the significantly increased hepatic artery
calibration and dilated hepatic artery branches in the liver parenchyma was shown in thorax
CT, the patient was recommended to be examined with contrast-enhanced abdominal CT.
Contrast-enhanced abdominal CT revealed an increase in liver size without splenomegaly,
ascites and portal hypertension findings, and the celiac trunk and the subsequent hepatic
arteries were widely dilated due to increased flow. The diameter of the portal vein, superior
mesenteric vein (SMV), and splenic vein were increased. (Figure 2). The patient was taken to
the catheter laboratory for right heart catheterization (RHC) to be examined for porto-
pulmonary hypertension and the measurements supported postcapillary pulmonary
hypertension (mean PAP: 28mmHg/PCWP: 22mmHg/PVR: 0.62 WU). Porto-pulmonary HT
was not detected. Selective angiography of the right renal artery showed multiple appearances
compatible with AV malformations extending to the liver (Figure 3). Pulmonary output (9.6
L/min), cardiac output (4.42 L/min), and shunt rate (Qp/Qs: 2.2) were calculated. Liver
Fibroscan (Transient Elastography) test revealed grade 4 fibrosis. Upper gastrointestinal
endoscopy revealed telangiectasias in the duodenal region. Diagnosis was made as Hereditary
Hemorrhagic Telangiectasia (HHT) based on Curaçao criterias. Cranial magnetic resonance
imaging (MRI) showed no cerebral AVM. A vascular endotelial growth factor (VEGF)
inhibitor, bevacizumab therapy 5 mg/kg dosing in every two weeks was initiated, control
RHC was planned for 6 months later. Beta-blocker, mineralocorticoid receptor antagonist
(MRA) and diuretic treatment were also started Her symptoms ameliorated under treatment.
At the fourth month of the therapy, Fibroscan testing was repeated and it demonstrated grade
2 fibrosis. In control RHC, mean PAP (18mmHg), PCWP (11mmHg) and Qp/Qs (1.6) values
were regressed. No significant pathology was found in the fluid loading test. The RHC
procedure was terminated with normal hemodynamic findings. The patient was externalized
with the current treatment and referred to routine outpatient controls.

Discussion

We presented a patient with pulmonary hypertension due to highoutput heart failure. HHT
whose symptoms improved with bevacizumab therapy. Genetic origin of HHT was revealed
in 1990s(11-13).Mutations that encode vascular endotelial transmembrane proteins as ALK-1
(Activin like receptor kinase 1) and endoglin. lead to increased activity of TGF-β1 which
induces VEGF level in HHT(14, 15). Thus, anti-VEGF therapies have been become an
important treatment choice for patients with HHT(8-10).

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody that

binds to all isoforms of human vascular endothelial growth factor-A (VEGF-A) and inhibits
VEGF activity and angiogenesis(16, 17). It is approved by the FDA in addition to standard
treatments of some solid cancers as ovarian cancer, colorectal cancer and renal cell
carcinoma(18-20). Its efficiency in treatment of HHT related complications have been
demonstrated in several studies(8, 9). Moreover, in a case report bevacizumab was found to
reverse need for liver transplantation in HHT with severe hepatic involvement(10).

Pulmonary hypertension (PH) in HHT is usually result of high output state due to hepatic
AVMs that is defined as post-capillary PH(2, 21). Also, HHT related mutations in endoglin or
ALK-1 gene less frequently may lead to pre-capillary PH(21). Differentiation between pre
and post-capillary PH can be assessed by right heart catheterisation (RHC)(21). Treatment
options differ regarding to type of PH in HHT. In our case, RHC findings were consistent
with post-capillary PH thus patient received diuretic treatment and salt restriction.

Optimal treatment of HHT with severe liver involvement and high-output state is a matter of
debate. Liver transplantation (LT) has been suggested in patients with liver VMs that lead to
develop intractable portal hypertension, intractable heart failure and ischaemic biliary
necrosis(1). Although it is shown LT improved cardiovascular function, perioperative and
postoperative complications and necessity of life-long immunosuppressive drugs limit its
utilization as the standard therapy(1). On the other hand, use of bevacizumab in the treatment
of HHT demonstrated some promising results(8, 9). Nevertheless, there is no consensus on
duration of induction therapy and necessity of constant maintenance treatment.

In two studies that investigated the efficiency of bevacizumab in patients with HHT, it was
demonstrated bevacizumab ameliorated symptoms related to cardiovascular dysfunction, yet
improvement in cardiac index was accomplished in %55 of 150 patients and %80 of 25
patients, respectively.(8, 9). In our case, it remains unclear whether the mean PAP, which was
high at the beginning, was regressed with diuretic or bevacizumab therapy. However,
considering the decrease in shunt rate (Qp/Qs), we thought this decline in mean PAP is due to
bevacizumab therapy. We also used liver Fibroscan testing before and after bevacizumab
therapy as a potent predictor in assessing treatment response to bevacizumab in patients with
HHT and liver involvement. It revealed that the degree of fibrosis diminished after
bevacizumab therapy. It can be suggested that the decrease in fibrosis degree in the fibroscan
test may reflect the decrease in liver congestion due to beneficial effects of bevacizumab
therapy. Close physical examination and related multimodality imaging help to diagnnose rare
diseases.

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Keywords: pulmonary hypertension, right heart catheterization, bevacizumab, osler weber

rendu, hereditary hemorrhagic telangiectasia

Funding

No record of funding for this case report was declared.

Conflict of interest

The authors have no conflict of interest.

Disclosures

The authors have no disclosures.

Legend of Figures

Figure 1. Purple coloured papules on lips and neck

Figure 2. Increased diameter of the portal vein, superior mesenteric vein, and splenic vein

Figure 3. AV malformations extending to the liver

Figure 1.
Figure 2.
Figure 3.