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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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Conflict of interest disclosure
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2013: Presentation at anotherhospital
• Exercise intolerance (NYHA 3)
• Palpitations
• Near collaps
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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
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Echocardiography: Severe Pulmonary HypertensionStandard diagnostic work up
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Echocardiography: Severe Pulmonary HypertensionStandard diagnostic work up
Hb: 11.1, ht:0.58, SaO2: 99%
Trombophilic lab: No abnormailities
Abnormal perfusiondefect LLL
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Pulmonary angiograpy
mPAP: 56 Mg, CI 3.9, PVR 8 WU. RAP 12 mmHg
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Additonal finding on CT
Hepatosplenomegaly
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Does the amount of clots explain the pulmonary hypertension?
• Yes
• No
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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.
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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
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2014: Progression of symptoms anddevelopment of pericardial fluid:
referral to our hospital
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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
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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
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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
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MRI of the right ventricle
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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
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What is your diagnosis?
• Antiphospolipid syndrome?
• Von Hippel-Lindau syndrome?
• Trombotic microangiopathy?
• POEMS syndrome?
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The effects of Long standing hypoxia
• Upregulation of erytropoietin :Erytrocytosis
• Upregulation of VEGF: Hepatosplenomegaly
• Hypoxic induced pulmonary hypertension
• Systemic vasodilation
• High cardiac output
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Living in the polderAnd still living at
High Altittude
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Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital PolycythemiaYves Pastore, AJHG 2003
HypoxiaNormoxia
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Mutations of von Hippel-Lindau Tumor-Suppressor Gene and Congenital PolycythemiaYves Pastore, AJHG 2003
HypoxiaNormoxia
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Genetic screening: Homozygotous mutation in
C152G>C mutation in exon 1 VHLC
What do we know about theconsequences of this mutation ?
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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
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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
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The chuvash experience
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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)
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Given this finding how would you treatour patient?
• Surgical removal of the clots
• Addition of a prostanoid
• Iron suppletion
• Oxygen suppletion
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Talbot NP et al, Physiol Rep. 2014:11;2.
SP
AP
The effect of iron on hypoxic pulmonary
vasoconstriction
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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
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The consequence of a VHL mutation
• Sensing hypoxia while inhaling normoxia
– Continuous hypoxic pulmonary vasoconstriction and pulmonary hypertension
– Systemic vasodilation (warm hands)
– Hypercirculation
– Polycythemia
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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.
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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
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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)
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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