Pulmonary hypertension with warm hands

A 19-year-old woman of Moroccan descent presented with severe dyspnoea on exertion. She had difficulty walking stairs (New York Heart Association functional class 3) and accompanying symptoms included fatigue, palpitations and near collapse. She had no cough or wheezing, but mentioned severe and continuous menstrual bleeds since menarche without use of contraceptives. Her medical history included long-standing complaints of fainting, abdominal pains and chest pain, without a clear diagnosis. The family history included hypercholesterolaemia and venous thromboembolic disease (VTE). In fact, 1 year prior to this presentation, the patient was diagnosed with PE herself. Other than a temporary mild polycythaemia (haemoglobin concentration of 16 g/dL) no risk factors for VTE had been discovered at that time. Physical examination showed a thin woman with a body mass index of 17 kg/m (height 161 cm and weight 44 kg). Her blood pressure was 82/51 mm Hg, while her extremities appeared warm. Her heart rate was 91 bpm, the respiratory rate 16/min and oxygen saturation (SpO2) 98%. Heart and lungs appeared normal, but abdominal examination revealed overt hepatosplenomegaly. There were no signs of peripheral oedema, venous thrombosis or clubbing. Routine blood chemistry showed a haemoglobin level of 16.0 g/dL, haematocrit 57%, a mean corpuscular volume of 72, reticulocyte index 18% together with a serum iron of 6.1 μmol/L and a ferritin of 7 μg/L, suggestive for anaemia secondary to severe iron deficiency, most likely due to hypermenorrhoea. The N-terminal pro brain natriuretic peptide level was elevated to 196 pg/mL. Thrombocytes, white blood cells, kidney function, liver enzymes and thyroid stimulating hormone were all within reference values (see online supplementary table S3). No abnormalities were noted on the chest radiograph; however, a transthoracic echocardiogram showed mild right ventricular (RV) dilatation and dysfunction, a tricuspid annular plane systolic excursion of 23 mm, an estimated RV systolic pressure of 57 mm Hg and right atrial pressure of 5 mm Hg. Furthermore, there was no evidence of paradoxical septal motion. Cardiac magnetic imaging (CMR) was performed which confirmed mild RV dysfunction with an RV ejection fraction of 47% (see online supplementary table S1). The RV appeared mildly dilated and hypertrophic, whereas no signs of valvular abnormalities or intracardiac shunts were noted. This pointed to a pulmonary cause of her RV dysfunction. Spirometry showed a total lung capacity of 3.97 L (4.84 L; 82%), residual volume of 1.08 L (1.31 L; 82%), FVC of 2.65 L (3.59 L; 74%) and a FEV1 of 1.75 L (3.13 L; 56%). Carbon monoxide diffusion capacity (DLCO) was 97.64 μmol/s/kPa (60%) and 6 min walking distance was 370 m with no drop in SpO2. Because of the suspicion of pulmonary hypertension (PH), a right heart catheterisation (RHC) was performed which confirmed PH with an elevated mean pulmonary artery pressure of 56 mm Hg, pulmonary arterial wedge pressure (PAWP) of 16 mm Hg with a moderately elevated pulmonary vascular resistance (PVR) 492 dyn·s/cm and decreased systemic vascular resistance (SVR) 742 dyn·s/cm (see online supplementary table S2). Pulmonologist 1: The differential diagnosis of PH is extensive. Causes for pulmonary arterial hypertension (PAH, WHO group 1) such as drugs, anorexins and toxins as well as portal hypertension were excluded. Although left heart conditions such as congenital cardiac defects and valve abnormalities were excluded by CMR, the PAWP was elevated which makes PH due to left disease still a possibility (WHO group 2). The DLCO was reduced and spirometry appeared abnormal, although the latter is probably a consequence of Caucasian reference values. The absence of abnormalities on chest imaging made chronic lung disease-related PH (WHO group 3) unlikely but additional imaging is needed. Given the history of PE, chronic thromboembolic pulmonary hypertension (CTEPH, WHO group 4) was clearly suspected and should be investigated by ventilation/ perfusion scintigraphy (V/Q scan). Finally, given the presence of hepatosplenomegaly, WHO group 5 PH (multifactorial mechanisms) is still a possibility although no additional findings point to this direction. A V/Q scan and CT angiography showed no perfusion defects besides in the left lower lobe due to residual thrombi. There was no evidence of parenchymal lung disease. A diagnosis of inoperable CTEPH was made and the patient was started on treatment with bosentan (125 mg twice daily), tadalafil (40 mg once daily; off-label use) and oral anticoagulants as standard CTEPH treatment. After 1 year on treatment, there was no improvement in exercise tolerance and the fatigue was unaltered. A repeated RHC showed a cardiac output of 13.0 L/min, a PVR of 176 dyn·s/cm, whereas the SVR was further decreased to 367 dyn·s/cm. The PAWP remained elevated (see online supplementary table S2). Subsequently, the patient requested a second opinion in our PH expert centre for specialised advanced knowledge on all types of patients with PH. Pulmonologist 2: A diagnosis of CTEPH may seem reasonable in a patient with PH, a prior VTE and perfusion defects, but in this patient the diagnosis can be