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A 19 year lady with pulmonaryhypertension and warm hands

Anton Vonk NoordegraafDept of pulmonary medicine

VU medical centerAmsterdam

The Netherlands

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2013: Presentation at anotherhospital

• Exercise intolerance (NYHA 3)

• Palpitations

• Near collaps

History

• From early childhood on: many clinicalpresentations: fainting, abdominal pain, chestpain

• 1999 Henoch-Schönlein.

• 2007 Hepatitis A together with an EBVinfection

• 2012: (acute) pulmary embolism

• 2013: Erytrocytosis: repeated flebography

Echocardiography: Severe Pulmonary HypertensionStandard diagnostic work up

Echocardiography: Severe Pulmonary HypertensionStandard diagnostic work up

Hb: 11.1, ht:0.58, SaO2: 99%

Trombophilic lab: No abnormailities

Abnormal perfusiondefect LLL

Pulmonary angiograpy

mPAP: 56 Mg, CI 3.9, PVR 8 WU. RAP 12 mmHg

Additonal finding on CT

Hepatosplenomegaly

Does the amount of clots explain the pulmonary hypertension?

• Yes

• No

Azarin R et al, J Nucl Med. 1997;38:980-3.

• CTEPH

o Acute PE

Lung perfusion scans and hemodynamics in acute and chronic pulmonary embolism.

Considerations of referral hospital

• CTEPH, however clots donot provide a goodexplanation of pulmonary hypertension

• Therefore uncertain whether patient willbenefit from surgery

• Initiation of double oral therapy

2014: Progression of symptoms anddevelopment of pericardial fluid:

referral to our hospital

At admission in our hospitalSymptoms

• Fatigue• shortness of breath while walking short distances (NYHA 3)• Palpitations• Weight loss (3 kg)• menorragie

Social history• moroccan girl• Mother and Father: nephew and niece• Worked as an administrator

Intoxications: none

Medication: bosentan 2 x 125 mg, tadanafil: 40 mg, acenocoumarol

Physical examination

• Weight: 46kg, Length: 1,62m

• RR 82/51 mmHg, although warm extremities, HF 91/min, BF: 16/min temperature: 37°C

• Heart + lungs no abnormalities

• Hepatosplenomegaly

• No edema

Lab investigations

• BSE 2 mm/hour• Hb 7,1 mmol/l• Ht 0,39 l/l• MCV = 66 (microcytair anemia)• Trombocyten 133 x10E9/l, • WBC 4,9 x10E9/l• Normal liver and kidney function• NT-proBNP 196 ng/l• TSH 4,1 mU/l. • Fe: 4.3• Iron saturation: 8 %

Conclusion: Anemia secondary to extreme iron deficiency

MRI of the right ventricle

List of unexplained symptoms and signs

• Hypotensive and anemic and still having warm hands

• Pulmonary hypertension with minimal clotload

• High Cardiac output

• Erytrocytosis in the past although nothypoxemic

• Hepatosplenomegaly

What is your diagnosis?

• Antiphospolipid syndrome?

• Von Hippel-Lindau syndrome?

• Trombotic microangiopathy?

• POEMS syndrome?

The effects of Long standing hypoxia

• Upregulation of erytropoietin :Erytrocytosis

• Upregulation of VEGF: Hepatosplenomegaly

• Hypoxic induced pulmonary hypertension

• Systemic vasodilation

• High cardiac output

Living in the polderAnd still living at

High Altittude

Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital PolycythemiaYves Pastore, AJHG 2003

HypoxiaNormoxia

Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital PolycythemiaYves Pastore, AJHG 2003

HypoxiaNormoxia

Genetic screening: Homozygotous mutation in

C152G>C mutation in exon 1 VHLC

What do we know about theconsequences of this mutation ?

VHL mutated Mice models shows pulmonaryhypertension not explained by polycythemia

Hickey, M. M., et al The von Hippel-Lindau Chuvash mutation promotes pulmonaryhypertension and fibrosis in mice. The Journal of clinical investigation, 120(3), 827–39

VHL mutated Zebra fish model shows increased cardiac output

Rooijen, E, Eeden, van F,J., Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia, Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands, Blood. 2009;113:6449-6460

The chuvash experience

The effect of hypoxia on VHL mutated patients

Frise MC and Robbins PA. Mini review: Iron, oxygen and the pulmonary circulation, JAP

2015 (in press)

Given this finding how would you treatour patient?

• Surgical removal of the clots

• Addition of a prostanoid

• Iron suppletion

• Oxygen suppletion

Talbot NP et al, Physiol Rep. 2014:11;2.

SP

AP

The effect of iron on hypoxic pulmonary

vasoconstriction

The effect of iron suppletion on ourpatient

Before After Iron (2015)

mPAP (mmHg) 56 mmHg 37mm Hg

RAP (mmHg) 13 mmHg 8 mm Hg

CO (l/min 6,3l/min 9.1 l/min

PVR (WU) 8 2.3

PCWP (mmHg) 12 17

Open question: should we not reduce PAH specific medication

The consequence of a VHL mutation

• Sensing hypoxia while inhaling normoxia

– Continuous hypoxic pulmonary vasoconstriction and pulmonary hypertension

– Systemic vasodilation (warm hands)

– Hypercirculation

– Polycythemia

Summary

• A mutation of VHL gen is a rare cause of pulmonary hypertension.

• Those patients exhibits the typicalcharacteristics of chronic hypoxia exposure.

• Iron modulates Hif-1α.

• Advances in science helps us to treat ourpatients in a different way.

List of unexplained symptoms andsigns explained

• Pulmonary hypertension, not explained byclot load: extensive hypoxic pulmonaryvasoconstriction

• Polycythemia: Increased levels of HIF1 alfa

• Hepatosplenomegaly: Increased VEGF

• Hypercirculation: low systemic resistance

• Despite the anemia and hypotension: warm hands: systemic vasodilation

Referenties• Formenti, F., Beer, P. a, Croft, Q. P. P., Dorrington, K. L., Gale, D. P., Lappin, T. R. J., 2011.

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation. FASEB 25(6)

• Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Polyakova, L. A. 2014. Congenital disorder of oxygen sensing : association of the homozygous Chuvashpolycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors, 103(10), 3924–3933

• Hickey, M. M., Richardson, T., Wang, T., Mosqueira, M., Arguiri, E., Yu, H., … Simon, M. C. 2010. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. The Journal of clinical investigation, 120(3), 827–39

• Imamura, M., Tsurumi, H., Hatanaka, K., Kawa, K., Suzuki, R., & Miyamura, K. (2014). To the editor : Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and, 117(13)

• Gordeuk, V. R. 2012. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia). Haematologica, 97(2), 193–200.

• Rooijen, E, Eeden, van F,J., Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands, Blood. 2009;113:6449-6460

• Smith, T G, Brooks, J. T., Balanos, G. M., Lappin, T. R., Layton, D. M., Leedham, D. L., Robbins, P. A. 2008. Mutation of the von Hippel-Lindau Gene Alters Human Cardiopulmonary Physiology, Adv Exp Med Biol. 605 (51–56)

• Smith, Thomas G, Brooks, J. T., Balanos, G. M., Lappin, T. R., Layton, D. M., Leedham, D. L., Robbins, P. a. 2006. Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonaryphysiology. PLoS medicine, 3(7)

Mice model

• Baseline respiration

• No change in cardiac response and cardiac muscle

Hickey, M. M., Richardson, T., Wang, T., Mosqueira, M., Arguiri, E., Yu, H., … Simon, M. C. 2010. The von Hippel-Lindau Chuvash mutationpromotes pulmonary hypertension and fibrosis in mice. The Journal of clinical investigation, 120(3), 827–39