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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