Spherocytosis and pulmonary hypertension J .

Eur Aesplr J
CASE REPORT
1991, 4, 629-631
Spherocytosis and pulmonary hypertension
coincidental occurrence or causal relationship?
D. Verresen, W. De Backer, J . Van Meerbeeck, I. Neetens, E. Van Marck, P. Vermeire
Spherocytosis and pulmonary hypertension, coincidental occurrence or causal
relationship? D. Verresen, W. De Backer, J. Van Meerbeeck, /. Neetens, E.
Van Marck, P. Vermeire.
ABSTRACT: A report is given on a 59 yr old man with hereditary
spherocytosis and progressive shortness of breath on exertion, due to
sever e pulmonary hypertension and cor pulmonale. An open lung biopsy
was per formed In order to exclude all known aetlologies of secondary
pulmonary hypertension. Pa thologica l examination r evealed in situ
thrombosis and asymmetric fibromuscular hyperplasia of small- and
medium-sized pulmonary arteries. Both primary pulmonary hypertension and hereditary spherocytosis have a low incidence in the general
population and their simultaneous occurrence has not been reported
previously; the possibility that this was due to a causal relationship and
not to coincidence cannot be ruled out, in view of some similarities with
pulmonary hyper tension complicating sickle cell anaemia,
Eur Respir J., 1991, 4, 629-631.
Depts of Respiratory Medicine and Pathology,
University Hospital, University of Antwerp (UIA),
Belgium.
Correspondence: D. Verresen, University Hospital
Antwerp, Wilrijkstraat 10, B-2650 Edegem,
Belgium.
Keywords: Pulmonary hypertension; spherocytosis.
Received: December 10, 1990; accepted January 16,
1991.
Pulmonary hypertension may be either primary or
secondary. The diagnosis of pr imary pulmonary
hypertension (PPH) requires the exclusion of any of the
several known causes of secondary hypertension [1-9).
We report the occurrence of pulmonary hypertension
in a patient with hereditary spherocytosis and
extramedullary haematopoietic tumours.
Case report
A Caucasian male, housekeeper aged 59 yrs, had been
experiencing progressive dyspnoea on exertion (New
York Heart Association grade II), for four months without wheezing or orthopnoea. He also had had a mild
chronic cough with sputum production, despite stopping a smoking habit of 20 pack-years one year ago. An
emergency hospitalization because of acute abdominal
pain at the age of 39 yrs had led to the diagnosis of
cholelithiasis and a nonspecified "blood abnormality".
His mother had died at the age of 30 yrs during a
gall-bladder operation and a niece had recently
undergone cholecystectomy and splenectomy for a
"haemolytic disease".
On physical examination at the time of referral the
only notable finding was a palpable spleen. A chest
radiograph demonstrated bilateral enlarged vascular hili
and decreased peripheral vascular lung markings.
Computerized tomographic (Cf)-scan of the thorax did
not show hyperinflation, suggestive of emphysema;
however, it showed tumoural opacities in both
Fig. 1. - Computerized tomographic (CT)-scan show ing an
in homogenous tumoural opacity in the left paravertebral area of the
thorax. A similar opacity was present more cranially/caudally on tbe
right side.
paravertebral areas (fig. 1). Routine pulmonary
function data were compatible with a mild obstructive
pattern (vital capacity (VC) 79%, residual volume
(RV) 166%, total lung capacity (TLC) 104%, forced
expiratory volume in one second (FEV1) 69% of predicted and a FEV 1NC ratio of 0.62) with a marked
decrease in diffusing capacity (Dco 46% of predicted).
Arterial blood gas measurement showed hypoxaemia
despite mild hyperventilation (arterial oxygen tension
(Pao2) 8.5 kPa, arterial carbon dioxide tension (PacoJ
4.4 kPa, pH 7.46, plasma bicarbonate 22.8 mmoH1).
630
D. VERRESEN ET AL.
The electrocardiogram indicated right axis and right
ventricular hypertrophy and these signs of cor pulmonale were confirmed by echocardiography. A lung
perfusion scan showed a markedly nonhomogeneous
perfusion but no typical signs of pulmonary embolism.
Exercising capacity during an ergometer test was
limited to 50 W; at this level maximal heart frequency
was 109 ~eats·min· 1 (67% of predicted) and maximal 0 2
uptake (Vo2max) 11.4 ml·min· 1·kg·1 (34% of normal
value), whereas 0 2 saturation measured by ear oximeter
had fallen from 98 to 91%.
Routine laboratory testing yielded a haemoglobin
concentration of 12.7 g·dl·1 and a white blood count of
8,000·mm·3 with normal differentiation. In addition there
was marked reticulocytosis (15%) and spherocytosis
(19%), with severely diminished osmotic resistance, low
haptoglobin concentration, negative direct Coombs
reaction and normal haemoglobin electrophoresis. Total
and direct bilirubin concentrations were 2.5 and 1.04
mg·dl· 1, respectively.
Abdominal echography showed cholelithiasis,
splenomegaly and a wide inferior vena cava. Right
heart catheterisation confirmed the presence of severe
pulmonary hypertension, with systolic, diastolic and
mean pulmonary artery pressures of 79, 19 and 39
mmHg, respectively; mean capillary wedge pressure was
12 mmHg. Pulmonary angiography showed severely diminished peripheral vascular filling without signs of
pulmonary embolism; on phlebography of the lower
extremities no signs of thrombosis were detected.
Fig. 2. -Lung artery (centre) showing almost complete obliteration
of the lumen and extensive fibromuscular thickening of the wall.
Masson's trichrome stain. Linear scale represents 100 ~-
A left thoracotomy was requested, both for biopsy of
the lung parenchyma in order to exclude known causes
of pulmonary hypertension, and for biopsy of a paravertebral tumour. The lingula biopsy showed an asymmetric fibromuscular hyperplasia of the small- and
medium-sized arteries, their lumen being nearly completely occluded by old organized and recanalized
thrombi (fig. 2). The paravertebral tumour consisted of
normal extramedullary haematopoietic tissue with
trilinear hyperplasia and relative predominance of the
red cell line. Mature univacuolar fat cells were also
present in the tumour. A subsequent crista iliaca
biopsy, performed to exclude other known causes of
extramedullary haematopoiesis, showed trilinear hyperplasia of bone marrow compatible with a haemolytic
syndrome.
The condition of the patient deteriorated rapidly during the following months, despite long-term home oxygen treatment and administration of a calcium-channel
blocking agent (nifedipine). Ten months after diagnosis
he was again admitted to hospital because of acute severe dyspnoea and he died suddenly a few hours later.
No autopsy was obtained.
Discussion
This patient presented with the rare combination of
hereditary spherocytosis and marked pulmonary hypertension, the latter progressing rapidly to death. Spherocytosis was causing characteristic features of a chronic
haemolytic syndrome with extramedullary haematopoiesis in pseudotumours located in both thoracic
paravertebral areas. He had cholelithiasis which is
another common finding in such patients [10-12]. His
pulmonary hypertension is to be considered as primary,
since known causes of secondary pulmonary
hypertension were excluded by open lung biopsy
findings; in particular there was no indication of repeated
pulmonary embolism and histological findings were
compatible with this diagnosis [1-9).
We were unable to trace any previous report of the
combined presence of both disease entities in the literature. By contrast, severe pulmonary vascular disease
has been reported in patients with sickle cell
haemoglobinopathies SS, SC and SB thalassaemia. In
such cases autopsy specimens have revealed asymmetric
intimal thickening and widespread occlusions of smalland medium-sized arteries with old, organized
recanalized thrombi. In these haemoglobinopathies red
cells are more rigid and nondeformable; they have also
been reported to bind to endothelial cells. Both features
cause increased blood viscosity and intrapulmonary red
cell sequestration, and they lead to vascular stasis and
even complete blockage of the microvasculature.
Pulmonary hypertension and cor pulmonale mostly
develop after multiple episodes of non-embolic pulmonary infarcts. Fat or necrotic bone marrow emboli
originating from extramedullary haematopoietic sites
have also been incriminated in this process [13-16).
One could wonder whether such in situ pulmonary
vascular occlusion could similarly have been caused by
the defect in red blood cell membrane formation present
in hereditary spherocytosis. This defect has been
attributed to a deficiency in spectrin, the largest and
most abundant structural protein of the red cell membrane skeleton, providing the flexibility and durability
necessary for the erythrocyte to resist the turbulences
inside the circulation. Spectrin deficiency in the membrane skeleton leads to a gradual loss of red cell surface
area, causing erythrocytes to become spherical instead
of remaining biconcave discs. Like sickle cells, such
erythrocytes are no longer deforming adequately in the
SPHEROCYTOSIS AND PULMONARY HYPERTENSION
microcirculation [12). One would thus envisage that this
disturbance also leads to in situ microvascular thrombosis, extensive vascular narrowing and occlusions,
resulting in pulmonary hypertension and cor pulmonale.
We were unable to detect in our patient any feature
that could have rendered him more prone to developing
pulmonary hypertension than other patients with
hereditary spherocytosis. Should one, thus, regard this
combination as a coincidental occurrence or as resulting from an unusual causal relationship? Both
non-embolic pulmonary hypertension and hereditary
spherocytosis are relatively rare conditions in the general
population. This would favour a causal relationship, and
such premise is strengthened by similarities with sickle
haemoglobinopathies. However, a hypothesis that hereditary spherocytosis be regarded as another cause
of secondary pulmonary hypertension would need
support from further observations.
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Sph~rocytose et hypertension pulmonaire, coi'ncidence ou
relation causa le? D. Verresen, W. De Backer, J. Van
Meerbeeck, I. Neetens, E. Van Marck, P. Vermeire.
RESUME: Expose de !'observation d'un homme de 59 ans
atteint de spherocytose hereditaire, et developpment d'une
dyspnee d'effort progressive due une hypertension pulmonaire
severe avec coeur pulmonaire. Une biopsie pulmonaire a ciel
ouvert est executee pour exclure toutes les causes connues
d'hypertension pulmonaire secondaire. L'examen anaromopathologique revele des thromboses in situ et une hyperplasie
fibro-musculaire asymetrique des arteres pulmonaires de petit
et de moyen calibre. L'hypertension arterielle pulmonaire
primaire et la spherocytose Mreditaire ont toutes deux une
incidence tres basse dans la population generale, et leur
presence simultanee n'a ete rapportee anterieurement. L'on ne
peut pas exclure la possibilite que cette presence simultanee
soil due a une relation de causalite plutot qu'a une coincidence,
puisqu'il existe certaines similitudes entre cette observation
et !'hypertension pulmonaire compliquant l'anemie falciforme.
Eur Respir J., 1991, 4, 629-631