CLINICO-PATHOLOGICAL CONFERENCE
A 38-year-old man with pulmonary hypertension,
who had undergone atrial septal closure 26 years previously
Toru Satoh, Takashi Yagi, Shinzo Kato, Koichiro Azuma, Masaharu Kataoka, Takao Takahashi1
Akiyuki Sato and Hajime Okita2
Departments of Medicine, 1Pediatrics and 2Pathology, School of Medicine, Keio University, Tokyo, Japan

Abstract. The patient was a 38-year-old man. He underwent atrial septal closure at the age of 12
years at Yokohama City University Hospital, when he already had pulmonary vascular change andreduced left-to-right shunt with Qp/Qs of 1.55 and pulmonary artery pressure (PA) of 56/22 mmHg.
Thereafter, he enjoyed running and skiing without any symptoms up until 32 years of age, when hedeveloped syncope due to severe pulmonary hypertension and atrial ﬂutter. PA was 116/57 mmHg andmRA was 13 mmHg on cardiac catheterization. He developed right heart failure and was referred to
Keio University Hospital on May 12th, 2001. Home intravenous prostacyclin infusion therapy was
introduced in addition to treatment for right heart failure. Echocardiography revealed a residualinteratrial shunt (from right to left). He recovered and was discharged. His condition worsened again
and he was readmitted to our hospital with chief complaint of visual disturbance due to digoxin intoxication, in addition to right heart failure. Despite aggressive treatment, he died of severe pulmonary
hypertension, right heart failure and congestive hepatic failure on December 10th, 2001. The differential diagnosis, pathophysiology and necessary treatment of pulmonary hypertension are discussed inthis paper. The clinical diagnosis was Eisenmenger syndrome due to atrial septal defect, and thepathological ﬁndings were compatible with this. (Keio J Med 52 (4): 250–262, December 2003)
Key words: right heart failure, Eisenmenger syndrome, prostacyclin, atrial septal defect, liver cirrhosis

Dr. Satoh (Moderator): Let’s start the 1055th clinicopathological conference (CPC). The patient was a 38year-old man. He was born in January 1963, and died at
the age of 38 last year. An ostium secundum type atrial
septal defect (ASD) was ﬁrst discovered at a medical
check-up in 1975, when the patient was 12 years old,and he underwent atrial septal closure at Yokohama
City University Hospital. Qp/Qs was 1.55, pulmonary
artery pressure (PA) was 56/22 mmHg, and mean rightatrial pressure (mRA) was 3 mmHg. The postoperative
course was uneventful. Around 1978, the patient moved
and stopped attending the hospital. Thereafter, heenjoyed running and skiing without any symptoms up
until to 32 years of age.
In 1995, at the age of 32, the patient developed syncope and fell while climbing stairs on his way to work.
He was admitted to Yokohama City University Hospital and found to have an intracranial hemorrhage. His
cardiac function was diagnosed as normal.

In 1997, he suffered a common cold accompanied bycough, expectoration and difﬁculty in breathing and was
re-admitted to Yokohama City University Hospital. PA
was 116/57 mmHg on cardiac catheterization, indicating
the recurrence of severe pulmonary hypertension, andmRA was 13 mmHg. There was no step-up of oxygen
saturation in any cardiac chamber. Severe (grade III)
tricuspid insufﬁciency was also noted. The symptoms
were relieved by administration of beraprost, enalapril,furosemide and digitalis, and the patient was discharged
from hospital.
In 1999, the patient developed syncope again with
palpitations and was admitted to Yokohama City University Hospital, where atrial ﬂutter was detected byelectrocardiography (ECG). This was suspected as being responsible for syncope. Direct current cardioversion was performed. Digitalis was discontinued, anddisopyramide and long-acting ISDN started.
The patient noted bilateral lower extremity edema

This is a record of the 1055th CPC of Keio University Hospital, held on October 9, 2002.
Reprint requests to: Dr. Toru Satoh, Cardiopulmonary Division, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan250

Keio J Med 2003; 52 (4): 250–262

and hepatomegaly in April 2001. He was referred to
Keio University Hospital on May 12th and admitted on
May 16th with the diagnoses of severe pulmonary hypertension (PH), tricuspid insufﬁciency and right heart
failure. Prostacyclin was introduced for PH, and furosemide, dobutamine and digitalis for right heart failure.
Atrial tachycardia was transiently observed for which
amiodarone was started. Cardiac gated radionuclide
ventriculography revealed low left and right ventricularejection fractions (EF) of 49% and 41%, respectively.
Echocardiography revealed a residual interatrial shunt(from right to left). His condition improved and he wasdischarged from hospital.
The patient was followed up in an outpatient clinic.
He steadily gained weight, lost his appetite and developed abdominal swelling and general malaise. His
symptoms gradually worsened and visual disturbanceappeared. He was admitted to our hospital on November 7, 2001 for further treatment.
Ms. Takahashi (K.) (5th-year student): Both the left
and right ventricular EF seem to have decreased on thisadmission. It is known that the EF of the left ventricle
does not decrease in primary pulmonary hypertension(PPH). Does this imply that left heart failure hadalready occurred?
Dr. Satoh: It should be clear from the X-ray andphysical examination ﬁndings on admission as towhether left heart failure was present or not. However,
it is highly probable that the very low left EF was due tothe deformation of the left ventricle caused by marked
dilation of the right ventricle.
Mr. Tamura (5th-year student): Intravenous prostacyclin was introduced to treat the pulmonary hypertension and the patient was discharged from our hospitalwith an improvement in his condition. Were there any
ﬁndings regarding the decline of pulmonary arterypressure?
Dr. Satoh: Several procedures can be used to tell any
decline in pulmonary artery pressure such as catheterization, electrocardiography (ECG), physical examination and laboratory examinations. In fact, pulmonary
artery pressure could not be recorded due to inabilityof the catheter to reach the pulmonary artery becauseof the marked dilation of the right atrium and rightventricle. Cardiac catheterization was not conducted
after that. Neither physical examination, ECG nor Xray ﬁndings showed any improvement in his pulmonary
hypertension.
Mr. Tamura: Was any treatment other than intravenous prostacyclin tried, such as administration of nitricoxide (NO)?
Dr. Satoh: NO inhalation is certainly one method,and other drugs of choice include calcium blockers.
Since NO administration is still exploratory, we mustobtain permission for its use from the Ethics Commit-

251

tee. In the present case, permission had not beenobtained at that time, and NO could not be administered.
Mr. Tamura: There was a residual shunt at the atrial
level. Was the shunt responsible for the development ofPH?
Dr. Satoh: There is a possibility that the residual
shunt could have induced Eisenmenger syndrome, but
the defect was very small, less than 1 cm in diameter.
Therefore, the possibility that the shunt was responsible for pulmonary hypertension was considered to below.
Mr. Oda (6th-year student): I would like to know thedata on renal function and serum potassium level when
he was admitted to Yokohama City University Hospitalin 1999.
Dr. Satoh: According to this patient’s referral letter,his renal function was normal and serum potassium
level was within the normal range. What kind of ASD
do you think this patient had, based on the hemodynamic data? Were the hemodynamic data typical of apatient with ASD?
Mr. Suzuki (5th-year student): This patient’s Qp/Qs
was more than 1.5, suggesting that ASD closure wasindicated. His pulmonary arterial pressure was high,also supporting the indication for surgery.
Dr. Satoh: Patients with an ASD often have pulmonary hypertension because of increased pulmonary
blood ﬂow. This patient’s Qp/Qs of 1.5 usually does notcause pulmonary hypertension based on increased pulmonary blood ﬂow, although a Qp/Qs over 1.5 indicatesa signiﬁcant left-to-right shunt and the requirement for
operation. This patient, however, had pulmonary hypertension of a moderate degree. What kind of pathophysiology do you think was present?
Ms. Takahashi: I think this patient had pulmonary
hypertension from the beginning.
Dr. Satoh: Do you mean that his pulmonary hypertension had no relation to the ASD?
Ms. Takahashi: I don’t think it was related.
Dr. Satoh: Then, you have to rule out diseases thatcan cause pulmonary hypertension other than ASD.
The ASD may have been incidentally associated with
one of them. There is, however, another possibility that
his ASD had a large amount of shunt, which caused
pulmonary arterial lesions, such as medial hypertrophy
and intimal hyperplasia. The resultant high pulmonary
arterial resistance would have reduced the amount ofshunt. The latter possibility is more probable. Should
shunt closure be performed when the pulmonary vascular lesions are advanced? The most typical indication
for shunt operation is Qp/Qs over 1.5 without vascularlesions. When pulmonary vascular lesions are present
and pulmonary vascular resistance is increased, therequirements for ASD closure are that Rp/Rs, the ratio

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of pulmonary arterial resistance to systemic resistance,is less than 0.5 with Qp/Qs more than 1.5, accompanied
by grade I or II of the Heath and Edwards classiﬁcationof pulmonary vasculature or a good response to pulmonary arterial dilators, which increase Qp/Qs. Thispatient fulﬁlled these requirements and underwent surgery.
He suffered from syncope. What do you think caused
this?
Ms. Takahashi: One possibility is that his pulmonary
hypertension worsened further, with reduced cardiac
output and the development of syncope. Arrhythmia
is another possibility because he later experienced syncope due to atrial ﬂutter.
Dr. Satoh: The causes of syncope are divided into
four types. One is cardiac syncope. Patients with pulmonary hypertension develop syncope because of inability of the pulmonary arteries to dilate in response to
an increase in cardiac output on exertion. The pulmonary arteries are normally very expandable and canincrease their ﬂow several fold. When patients withpulmonary hypertension exercise as a normal person
would, they cannot achieve an increase in ﬂow, resulting in reduced blood pressure and the developmentof syncope. The second possibility is arrhythmia. Are
there any other causes?
Ms. Takahashi: Other causes are vasovagal syncope
and syncope due to orthostatic hypotension.
Dr. Satoh: Those are other possibilities. The patient
took two or three vasodilators, which might have caused
a reduction in blood pressure and orthostatic hypotension. Patients with pulmonary hypertension are known
to be prone to developing vasovagal reﬂex.
Ms. Takahashi: I think that cerebral emboli might
have been the cause.
Dr. Satoh: If cerebral emboli had occurred, whatkind of condition do you think he had?
Ms. Takahashi: I think that atrial ﬁbrillation may
have been responsible for that.
Dr. Satoh: Another possibility is that paradoxical
emboli from the right to the left atrium were a source of
cerebral emboli.
This patient was administered IV prostacyclin. It has
been used for three years in Japan, and since 1991 in
the USA. Do you know what kind of drug it is?
Mr. Takahashi (M.) (5th-year student): Prostacyclin
dilates the pulmonary arteries and has an antithrombotic action.
Dr. Satoh: Prostacyclin is present in normal humans
and can be synthesized through biotechnology. I would
like to explain the characteristics of this drug brieﬂy.
This drug has to be constantly administered intravenously because of its short half-life. A catheter isinserted into the subclavian vein, passed subcutaneously, and exits through the chest wall skin. It is

Satoh T, et al: Pulmonary hypertension patientconnected to an ambulatory infusion pump, which
delivers a determined amount of drug (Fig. 1). I haveused this therapy in ten patients. Seven of them showed
improvement, while the remaining three did not show amarked improvement and their condition deteriorated.
Dr. Yagi, I heard that a small opening was present in
the operated atrial septum. What was the size of the
opening?
Dr. Yagi (Cardiology): The size was not measured
accurately. There are two methods of ultrasonographic
examination of the heart; transthoracic echocardiography and transesophageal echocardiography. Transesophageal echocardiography yields more detailed information on the heart, but it was not conducted inthis patient at our hospital. Only transthoracic echocardiography was conducted. The size of the atrial septal foramen was not measured. A shunt was observed,
but the foramen seemed to be very small.
Dr. Satoh: Was it less than one centimeter in diameter?
Dr. Yagi: It was not actually measured, but possibly
it was.
Dr. Satoh: Let’s change the subject. I would like toreturn to the cause of syncope. Following the syncopal
attack, he had an intracranial hemorrhage. What do you
think were the causes of the syncope based on this fact?
Mr. Takahashi (M.): I think that the cerebral hemorrhage was due to embolism.
Dr. Satoh: Dr. Kataoka, from the Cardiopulmonary
Division, what is your opinion?
Dr. Kataoka (Cardiology): The intracranial hemorrhage was caused by some injury. The existence of injury means that there was a very short time interval
between the onset of the cause and the actual syncope.
Dr. Satoh: As explained by Dr. Kataoka, injury usually occurs when the patient cannot respond properly
to an event when syncope is about to develop. Injury
accompanied by syncope leads us to consider that theorigin was cardiac.
By the way, the patient noticed visual disturbancejust before admission. The main reason for this admission was actually worsening of right heart failure.
However, his chief complaint was visual disorder. Whatdo you think was the cause?
Mr. Takahashi (M.): He showed signs of right heart
failure such as jugular venous distension with a prominent v wave. I think that venous congestion induced
papilledema, resulting in visual disturbance.
Dr. Satoh: Dr. Takahashi, a pediatric neurologist,
have you ever seen a patient with right heart failure
accompanied by papilledema?
Dr. Takahashi (Pediatrics): I have never encountered such a case.
Dr. Satoh: That does not usually occur. Let’s think
about it later after looking at the laboratory data. Dr.

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Fig. 1 Ambulatory continuous prostacyclin treatment. Left upper: The way the catheter is inserted. Left lower: The way a patient carries anambulatory infusion pump for prostacyclin. Right: An ambulatory infusion pump. It is put inside the bag. A pump is compared to a felt marker.

Yagi, will you describe the ﬁndings of physical examination on admission and the laboratory data?
Dr. Yagi: On admission, the patient’s height was 173
cm, weight 57 kg and the circumference of his abdomen
was 89 cm. His blood pressure was 105/60 mmHg, witha pulse of 51 bpm. Positive ﬁndings were as follows.
The conjunctivae showed mild jaundice, and the jugularvein was visible 20 cm above Louis’ angle. The v wavesof the jugular vein were prominent, and there was attenuation of the ﬁrst heart sound and increased IIp. A
third heart sound was audible and showed the RiveroCarvallo sign. A fourth heart sound could not be heard.
A III/IV murmur was heard at the 4th intercostal space
and the left margin of the sternum, and showed theRivero-Carvallo sign. A diastolic murmur I–II/VI was
also heard at the 2nd intercostal space and the left
margin of the sternum, but the Rivero-Carvallo sign
was unclear. Right ventricular heave was palpable, andthe lung ﬁelds were clear. The abdomen was considerably swollen, as already noted from its circumference.

A tympanic sound was heard on percussion, and ﬂuctuations were also noted. The liver was palpable 2 ﬁnger-breadths below the right costal margin, with notenderness. The spleen was not palpable. Edema waspresent in both legs.
In the laboratory data, the platelet count in peripheral blood was slightly low at 99,000. Prothrombin time(PT) was low at 36%. Clinical chemical data included
total bilirubin (TB) of 2.9 mg/dl, showing an indirect
dominance. Urea nitrogen (UN) was 39.2 mg/dl andcreatinine (Cr) was 1.3 mg/dl. The UN/Cr ratio was increased. Alkaline phosphatase (Alp) level was 509 U/Land amylase (AMY) 721 IU/L, both elevated. Brain
natriuretic peptide (BNP) was 1131 pg/ml, which wasmarkedly elevated as compared to the normal value ofapproximately 30 pg/ml. As for thyroid function, freeT3 (FT3) and free T4 (FT4) were slightly low. Thyrotropic hormone (thyroid stimulating hormone: TSH)
was markedly elevated to 35.2 mIU/l. Blood gas analysis showed partial pressure of carbon dioxide (pCO2 )254

of 28.4 Torr and partial pressure of oxygen (pO2 ) of
57.1 Torr, both decreased. There was no acidosis, andHCO3  was 19 mEq/L. Blood concentration of digoxin
was elevated at 3.9 ng/ml.
Analysis of ascitic ﬂuid on admission revealed acell count of 334 /mm 3 and glucose concentration of
114 mg/dl, which were normal. The protein level washigh at 2.1 g/dl, and lactate dehydrogenase (LDH)
991 IU/L. AMY was 411 IU/L, CEA 2.6 ng/ml, andCA19-9 8 U/ml. Antinuclear antibody (ANA) was negative and alcohol dehydrogenase (ADA) was 1.5 IU/L.
Mr. Tamura: I would like to conﬁrm whether he wasgiven coumadin because his INR increased to 1.91.
Dr. Yagi: The patient was taking warfarin on admission.
Mr. Tamura: Could you tell me whether he had liver
dysfunction?
Dr. Yagi: Yes, he did.
Mr. Tamura: Chronic pulmonary thromboembolism
has to be ruled out in the differential diagnosis of pulmonary hypertension. Did you perform any investigations to examine this?
Dr. Yagi: No, this was not possible because of thepatient’s poor general condition. I cannot say deﬁnitely,
but since the patient was treated with warfarin, thepossibility is considered to be low.
Dr. Satoh: It was ruled out based on the ﬁndings of
pulmonary perfusion scintigraphy conducted earlier.
Dr. Sato (A.) (Internal Medicine resident): Was
neurological examination done?
Dr. Yagi: There was no distinct hemiplegia or facial
asymmetry. As for visual acuity disturbance, the patientcomplained of inability to focus properly.
Dr. Satoh: What kind of pathological condition do
you think the patient had, based on the physical ﬁndings and laboratory data?
Ms. Takahashi: First I would like to refer to thephysical ﬁndings. I think he had pulmonary hypertension because he had an accentuated P2 on auscultation. He had right heart overload due to pulmonary
hypertension and tricuspid regurgitation with RiveroCarvallo sign. He had ascites judging from ﬂuctuation
on abdominal palpation. Jaundice of the conjunctivae
and an engorged liver indicated liver congestion. All
these ﬁndings as well as leg edema indicated that he hadright heart failure. Laboratory data revealed liver dysfunction judging from increased bilirubin, LDH and
AlP. An increase in KL6 indicated a pulmonary interstitial lesion. Reduced thyroid function may have been
due to sick thyroid syndrome derived from severe rightheart failure and progressive liver dysfunction. Hyperventilation was indicated by decreased PCO2 . His
digitalis level was far above the therapeutic range. It
was concluded that he had liver dysfunction, thyroid
hypofunction, pulmonary hypertension and right heart

Satoh T, et al: Pulmonary hypertension patient

failure.
Dr. Satoh: I appreciate your analysis. One thing I
want to comment on is whether his hypothyroidism
really was due to sick thyroid syndrome or not. The
second comment is that his liver dysfunction was considered to be due to right heart failure. Is that true?
Dr. Kato, from the Gastroenterology Division, would
you comment on this patient’s liver dysfunction? Can
we attribute it to cardiac congestion?
Dr. Kato (Internal Medicine): I think there is no real
problem with the interpretation. Some doctors may
have some doubts about the GOT and GPT levels,
which were not elevated in spite of hepatopathy. GOT
and GPT are elevated in patients with heart failure
when the hemodynamics suddenly worsen or the bloodpressure suddenly rises. In other words, GOT and GPT
are elevated in situations where hepatic necrosis occurs. When the liver becomes congested as a result of
the gradual progression of right heart failure, GOT or
GPT may occasionally not be elevated in a considerable number of cases. Concomitantly, bilirubin level isslightly increased in patients with liver congestion, andpersists for a long period. In such cases, Alp level isalso markedly increased. These ﬁndings of liver function tests may be characteristic of liver congestion.
Dr. Satoh: When biliary enzymes and bilirubin areelevated, but not serum GOT and GPT, liver dysfunction can be attributed to right heart failure.
Dr. Kato: The possibility of a congested liver being
responsible for hepatopathy is also reasonably high. In
this case, however, cholestasis due to drug-induced
hepatitis etc. must be considered in the differential diagnosis. This is naturally taken into consideration in
making the differential diagnosis, but if the time of its
occurrence is consistent with the time of exacerbationof the pathological condition due to right heart failure,
hepatopathy accompanying liver congestion should beconsidered the ﬁrst choice.
Dr. Satoh: Thank you for your explanation. One of
the students said that thyroid dysfunction was diagnosed as sick thyroid syndrome. Dr. Azuma, an endocrinologist, could you comment on the endocrinologicalabnormality?
Dr. Azuma (Internal Medicine): Euthyroid sick syndrome (low T3 syndrome) is a condition in which alow FT3 level is observed without thyroid abnormality
in patients with systemic disease or malnutrition, and isconsidered a kind of biodefense mechanism. Naturally,
it does not require supplementation of thyroid hormone. In some severe cases, FT4 may also be decreased,
but it is rare that TSH exceeds 10. The present patientwas certainly in a state of serious heart failure with livercirrhosis, FT4 was low and TSH exceeded 20. Since
thyroid hormone supplementation was considered necessary, the patient’s condition should be clinically con-

Keio J Med 2003; 52 (4): 250–262

255

Fig. 2 An electrocardiogram on admission. Refer to the text for
detail.

sidered to be hypothyroidism. As for whether or not
the patient had Hashimoto disease, this would not beknown, unless the appropriate autoantibody could bedetermined. Amiodarone may occasionally induce mild
hypothyroidism because it contains a high level of iodine. However, it is believed that TSH rarely exceeds
10 in the absence of some disposition towards hypothyroidism.
Dr. Satoh: One of the chief side effects of amiodarone is hypothyroidism, but hyperthyroidism may also
occur. So this patient’s hypothyroidism may have beencaused by amiodarone. Dr. Azuma argued that hypothyroidism of this degree may not have been caused
by amiodarone alone, but may have been caused by
Hashimoto disease from the start. This patient may
have had primary pulmonary hypertension (PPH). A
certain percentage of cases of PPH are complicated by
Hashimoto disease.
Dr. Kato: Since amiodarone frequently induces hepatopathy, drug-induced hepatopathy also has to be considered in making the differential diagnosis. However,hepatic function showed a slight elevation of bilirubin
and Alp about one year before the use of the drug.
Therefore, these ﬁndings can be regarded as being attributable to chronic liver congestion.
Dr. Satoh: What were the electrocardiographic ﬁndings (Fig. 2).
Mr. Takahashi (Y.) (5th-year student): The rhythm
looks like atrial ﬂutter. The electrical axis is right judging from leads I and aVF. There is right ventricular hypertrophy because the R wave voltage in V1 is morethan 0.7 mV.
Mr. Suzuki: The RR interval is not strictly regular,
but shows roughly 5 to 1 conduction. So I think it isatrial ﬂutter.
Dr. Satoh: Well, the RR interval is almost regular, so

Fig. 3

Chest X-ray on admission. Refer to the text for detail.

isn’t it sinus rhythm? If the RR interval is regular, therhythm can be sinus rhythm or atrial ﬂutter. Of course,
ventricular tachycardia is another possibility. If thisrhythm were sinus rhythm, a P wave would precede the
QRS complex. When you look at lead II or V1, you canﬁnd something like P waves. But they are more likesawtooths. You can also ﬁnd them between the QRS
complexes. These sawtooth-like conﬁgurations are ﬂutter waves. There is one QRS complex among three
ﬂutter waves, suggesting 3 to 1 conduction of atrial
ﬂutter. Usually the rate of ﬂutter waves is around 300
per minute. This patient’s rate was 150, which was very
slow. This may have been caused by amiodarone. LeadV6 shows a deep S wave, suggesting that the patient
had right ventricular hypertrophy.
Let’s move to the roentgenographic ﬁndings. What
were the ﬁndings (Fig. 3).
Mr. Tada (5th-year student): His cardiothoracic ratio(CTR) is 0.7, which is over the normal range of 0.5. The
cardiac shadow is widened in a right to left direction,suggesting right ventricular enlargement.
Ms. Takahashi: The second cardiac arch, indicating
the main pulmonary trunk, and the right second arch,which is the right atrium, are dilated.
Dr. Satoh: I will explain the additional ﬁndings. The
left ﬁrst arch is somewhat small, as reported in ASD.
The pulmonary ﬁelds are very clear, indicating scanty

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Fig. 4

Satoh T, et al: Pulmonary hypertension patient

Abdominal X-ray on admission. Refer to the text for detail.

pulmonary vessels. The vessels appear tapered, suggesting pulmonary hypertension. There also is pleurisy.
The dilated left 4 th arch shows right ventricular dilatation because it crosses the diaphragm in a right obliqueand downward direction.
So what were the ﬁndings of abdominal roentogenography (Fig. 4).
Ms. Takahashi: There is a difference in lucency between the X-rays taken on standing and in the recumbent position, indicating the presence of ascites. Also
intestinal gas appears dilated.
Dr. Kato: Increased intestinal gas, which is not
explained only by the presence of ascites, was observed.
Since a small amount of intestinal gas was observed, I
would consider congestion of the small intestine fromthe plain roentgenographic ﬁndings of the abdomen. I
suspect hypokinesis of the small intestine which is akind of ileus in such cases.
Dr. Satoh: Dr. Yagi, will you explain the clinicalcourse after admission?
Dr. Yagi: Digoxin was discontinued because theblood level of digoxin was high on admission. In orderto improve his right heart failure, the dose of furosemide was increased, and dobutamine was administered. The patient’s appetite subsequently improved.
There was also an improvement in his visual acuity.

However, oxygen saturation was not improved. The
amount of O2 administered could not be reduced to lessthan 80%. Since the hematological data showed atendency toward intravascular dehydration caused bydiuretics, the diuretics were withdrawn on November
21. On around November 24, the abdominal swelling
started to increase, together with a decreased blood
oxygen saturation. Diuretics were started again at alower dose. The ascites were drained by puncture whennecessary to decrease abdominal swelling.
Heart-lung transplantation was considered and an
attempt to improve the patient’s general condition was
made, but the blood oxygen saturation gradually
decreased. On November 29, disturbance of consciousness developed. Since the blood ammonia concentration was elevated, the patient was diagnosed as having
hepatic encephalopathy. The diuretics were withdrawn,
and Aminoleban, Monilac, and Kanamycin were administered. The hepatic encephalopathy was temporarily relieved, but right heart failure and low output
remained. The symptoms tended to gradually worsen.
On December 4, FT3 was 0.9 pg/ml, FT4 40.4 ng/dl,
and TSH 77 mIU/ml, showing exacerbation of hypothyroidism. Although there was a risk of an increasein peripheral oxygen consumption, low-dose thyroid
supplementation was started. On December 6, the urine
volume started to decrease. Fluid infusion or administration of diuretics was conducted according to thepatient’s condition, but he did not respond favorably,and died on December 10.
Dr. Sato (A.): Could you show the potassium
values?
Dr. Yagi: The potassium concentration was determined almost every day and was maintained at approximately 4.0 mg/L by intravenous potassium supplementation.
Dr. Kato: How about the nutritional state? I mean,
how was feeding conducted? And one more point, howwere his bowel movements?
Dr. Yagi: Bowel movements were stimulated withcathartics, Mentha fermentations, and so on, but werevery infrequent. As you said, there may be a possibility
that the decreased bowel movement triggered hepatic
coma. The patient’s nutritional state was not satisfactory, but he did not wish to receive intravenous hyperalimentation (IVH). Therefore, oral feeding was conducted with approximately 1/3 to 1/2 the amount of thenormal daily diet.
Dr. Kato: In protein equivalents, how many calories
were given, when feeding corresponding to about 1/2
the diet was conducted?
Dr. Yagi: A diet for heart failure patients was prepared. So, the patient was receiving half of 1800 Cal,i.e., 900 KCal or less, I think.
Dr. Satoh: How about the protein content?

Keio J Med 2003; 52 (4): 250–262

Dr. Kato: In the diet for heart failure, the protein
content is about 70 g. Since half of 70 g was ingested,
the amount was not so high. However, was any procedure instigated for feeding such as amino acid transfusion by drip infusion or any other means?
Dr. Yagi: Amino acid transfusion was not conducted.
Dr. Satoh: He had a good appetite and ate at least
half of every meal until he became unconscious.
Ms. Yamada (6th-year student): What kind of pathophysiology do you think was responsible for the arterial hypoxia? Could you show us the chest X-ray at thattime?
Dr. Yagi: The chest roentgenogram revealed no remarkable change in the lung ﬁelds to account for the
low oxygen saturation. CTR, however, had been gradually increasing. Identifying the cause of hypoxemia
remains a problem. It may have been associated withpulmonary hypertension, or the following mechanism is
a possibility. I believe that since severe tricuspid insufﬁciency was present, the blood did not ﬂow toward thelungs but ﬂowed toward the right atrium because ofhigh pulmonary vascular resistance, even if the rightventricle contracted. For this reason, the low cardiac
output state in the pulmonary circulation could havebeen responsible for hypoxemia.
Dr. Satoh: I would like to add that the ascites could
have prevented diaphragmatic movement and caused
alveolar hypoventilation, leading to hypoxia. The rightto left shunt may have increased and induced hypoxia
because of elevated right atrial pressure due to worsened pulmonary hypertension. Reduced pulmonary
ﬂow owing to severe pulmonary hypertension can cause
ventilation-perfusion inequality, resulting in hypoxia.
He had visual disturbance just before admission.
What do you think was responsible for it?
Dr. Yagi: The main cause of the visual disturbance
may have been a side effect of digoxin, judging from theclinical course. Another possibility may have been cerebral dysfunction due to hypoxia. However, the main
reason for the visual disorder can be considered to bedigoxin.
Dr. Kato: Were any unusual ﬁndings observed in theocular fundus?
Dr. Yagi: We consulted an ophthalmologist, butthere were no speciﬁc abnormalities in the eyes themselves.
Dr. Satoh: I think the visual disturbance was almost
certainly caused by digitalis intoxication, because his
vision recovered to normal when the high dose of digitalis was reduced. He became unconscious on November 29 th . What was the cause?
Mr. Takahashi (M.): I think that it was due to hepaticcoma, because the serum ammonium concentration wasmarkedly elevated due to reduced degradation of ammonium in the disordered liver, and this ammonium

257

would have entered the brain through the brain-blood
barrier.
Dr. Satoh: What was the ﬁnal diagnosis?
Ms. Takahashi: His main problem was right heart
failure. When the diuretics were stopped because of
dehydration and resultant hepatic coma, right heart
failure ensued. If the diuretics had been continued,
hepatic coma would have occurred. These conditions
drove him into a corner and caused his death.
Dr. Satoh: You think that he died of right heart failure? What was the cause of right heart failure?
Ms. Takahashi: I think that his pulmonary hypertension caused right ventricular dysfunction and that it was
already very severe when he underwent ASD closure,and worsened further after that.
Ms. Takahashi: If he had had Hashimoto disease oranother autoimmune disease, it may have contributed
to the pulmonary hypertension.
Dr. Satoh: We can conclude that he had Eisenmenger syndrome, can’t we? What is your opinion on
the cause of his pulmonary hypertension?
Dr. Yagi: It seems difﬁcult to differentiate the causesof pulmonary hypertension in this patient. I am not surewhether Eisenmenger syndrome was really present or
not, because he was not followed up frequently after hisheart surgery. Therefore, we must examine whether
the surgery was successful or not is a problem. There isanother possibility; anomalous pulmonary venous
drainage may have been associated with ASD, thereby
inducing Eisenmenger syndrome. This possibility cannot be ruled out, either. However, it seems highly
probable that PPH was responsible for his disease.
Laboratory tests ruled out collagen diseases, chronic
pulmonary thromboembolism, and angiitis. Other tests
ruled out angiitis, aortitis syndrome, idiopathic portal
hypertension, and liver cirrhosis. Therefore, diseases
leading to secondary pulmonary hypertension wereruled out.
Dr. Satoh: PPH and Eisenmenger syndrome remain
as the ﬁnal differential diagnoses. ASD was the cause of
Eisenmenger syndrome. Eisenmenger syndrome due to
ASD is different from that due to VSD or PDA. A large
shunt causes Eisenmenger syndrome in VSD or PDA,
whereas in ASD, Eisenmenger syndrome occurs without a large shunt. The mechanism of pulmonary hypertension is considered to be different between those
two types of congenital shunt. Some doctors think that
Eisenmenger syndrome due to ASD is merely a combination of ASD and PPH. However, the duration of theclinical course seemed too long for PPH. In typical
PPH, the 5-year survival is 27%.1 Patients with Eisenmenger syndrome secondary to ASD develop the disease in their teens or 20s and usually live until their 40s
or 50s.
We would like to discuss the treatment of hypo-

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thyroidism and severe liver dysfunction in this patient.
First, Dr. Kato, would you comment on the treatmentof liver dysfunction?
Dr. Kato: Treatment of heart failure takes ﬁrst priority over ascites, because ascites is considered to originate from congestion. I have another doubt about theoccurrence of hepatic encephalopathy in this patient,because neither GOT nor GPT was markedly elevatedon admission. Despite the fact that GOT and GPT were
only very slightly elevated, hepatic encephalopathy
rapidly worsened. At this point, what was the ammonia
level?
Dr. Yagi: It was about 100.
Dr. Kato: It wasn’t very high, was it? I don’t thinkthat this patient had acute hepatic failure, but I think heprobably had hepatic ﬁbrosis or was heading in that direction. The fact that GPT and GOT were only slightly
elevated suggests the absence of liver necrosis. Thismay be different from hepatic failure with fulminant
exacerbation. The presence of a chronically congested
liver induces hepatic ﬁbrosis and a decrease in hepaticfunction to some degree. In such cases, a massive
amount of ammonia ﬂows into the body from the intestine in the presence of congestion of the small intestine, resulting in failure of adequate treatment. This is
the mechanism by which hepatic encephalopathy wasconsidered to have developed in the patient.
Dr. Satoh: Do you consider that abnormality of thesmall intestine, rather than hepatic disorder, caused thecoma?
Dr. Kato: The small intestine rather than the liver
may be an important factor in hepatic encephalopathy.
As far as the liver is concerned, an acutely deterioratingchange such as necrosis may not have occurred widely
during the course of this patient’s disease.
Dr. Satoh: Is the treatment for coma caused by small
intestinal disorder different from that due to liver dysfunction?
Dr. Kato: Let me see. Intestinal movement andenteral disinfection (as described here) are enumerated
as treatment. It may be most important to induce defecation by intestinal movement with lactulose or lactitol.
Dr. Satoh: Thank you very much for your explanation. Regarding the treatment of hypothyroidism combined with heart disease, treatment of hypothyroidismor thyroid supplementation may sometimes aggravateheart failure because of increased oxygen consumption.
Dr. Azuma, would you please comment on this?
Dr. Azuma: A recent review in the New England
Journal of Medicine (Feb., 2001) has also shown that
hormonal supplementation in hypothyroidism increases
cardiac output and alveolar ventilation and decreases
vascular resistance, and that it has beneﬁcial effects
on cardiac and pulmonary function. In the elderly and

Satoh T, et al: Pulmonary hypertension patient

Fig. 5 Clinical course after the operation of the patients with atrial
septal defect and pulmonary vascular disease. Ten patients, who had
pulmonary hypertension deﬁned as their mean pulmonary pressure ofmore than 40 mmHg after ASD operation, were followed. Three patients were aggravated. Two patients were not changed. The remaining 4 patients were improved. Two patients died.

patients with heart disease, however, hormonal supplementation should be started at a low dose, taking
into consideration the increase in pressure on the heart
along with the increase in oxygen consumption. The
dose must be gradually increased under careful observation.
Dr. Satoh: What was the starting dose?
Dr. Azuma: There was no problem with 12.5 mg as
the initial dose.
Dr. Satoh: I would like to make a last comment. The
patient’s mean pulmonary arterial pressure was around
40 mmHg just before ASD closure. The prognosis ofpatients with an ASD and pulmonary vascular damage
depends on the pulmonary pressure. From my research,patients with a mean pulmonary pressure of less than 40
mmHg have a very good prognosis. Some patients witha value of more than 40 mmHg had improved or notchanged at ten years after the operation, while somedied within ten years (Fig. 5). I could not ﬁnd any goodparameters to differentiate patients with these different
prognoses. Dr. Ohkita, would you explain the pathological ﬁndings?
Dr. Okita (Pathology): The pathological diagnosis
is shown in Table 1. The main lesion was pulmonary
hypertension. The pathological ﬁnding in the lungs was
plexogenic pulmonary arteriopathy. Such an arterial
lesion forming a plexiform lesion is a pathological condition observed in PPH and pulmonary hypertension
secondary to congenital heart disease including ventricular septal defect and patent ductus arteriosus,
which are associated with increased pulmonary blood
ﬂow. Although rare, such an arterial lesion may be
induced by drugs or observed in chronic hepatic disease, HIV infection, etc.

Keio J Med 2003; 52 (4): 250–262
Table 1259

Autopsy Findings

1. Pulmonary hypertension (380 : 380 g)
1) Plexogenic pulmonary arteriopathy
Heath and Edwards grade: V
Plexiform lesion,
chronic dilatation lesion with vein-like arteries,
hemosiderin deposition
2) Pulmonary artery atherosclerosis3) treatment: prostacyclin
2. Core pulmonale (620 g)
1) Dilatation and hypertrophy of the right ventricle
right ventricular wall thickness: 7 mm
left ventricular wall thickness: 10 mm2) Dilatation of the right atrium
3. Chronic and acute congestion of the liver þ Hyperplastic nodule(1830 g)1) Congestion and ﬁbrosis in zone 3
2) Two hyperplastic nodules, left lobe, 12 mm, 6 mm
4. Ascites (5500 ml)
5. Atrial septal defect, 26 years after surgery
A slit-like defect in the posterior aspect of the sutured area

It is impossible to differentiate PPH from pulmonary hypertension accompanying congenital heart disease only from the histopathological ﬁndings in thelungs. In the present patient, differentiation of PPH
from pulmonary hypertension secondary to ASD became an issue, but it is impossible to determine this only
from the ﬁndings in the lungs. The clinical course also
needs to be considered in the differentiation.
The lesions marked as 2) in No. 1, No. 2, No. 3, andNo. 4 were associated with pulmonary hypertension,i.e., they showed atherosclerosis of the pulmonary
artery, or pulmonale, chronic congestion of the liver,and ascites, respectively.
The Heath and Edwards Classiﬁcation is essentiallya classiﬁcation of the severity of pulmonary vascularlesions accompanying congenital heart disease. Subsequently, it has been used to indicate the severity of
PPH. The severity is classiﬁed as grades I through VI.
This patient had grade V. Grade I and II are consideredreversible. Grade III or higher is considered irreversible. Grade I lesions show thickening of the tunica media of arterioles and small arteries of the lungs. GradeII lesions show cellular hyperplasia of the small arteries
and thickening of the tunica intima, which are due tothe cellular hyperplasia. Grade III lesions show almost
complete obliteration of small arteries, which is due
to ﬁbrous thickening of the tunica intima. Grade IVlesions show formation of plexiform lesions. Grade V
lesions show plexiform lesions and dilatation of arteries, the walls of which become thin like the wall ofa vein. Grade VI lesions show necrotizing vasculitis.
A plexiform lesion is deﬁned as follows: A small
pulmonary artery is dilated, in association with thickening of the tunica intima; and hyperplasia of heman-Fig. 6 Cut surface of the lung. Pulmonary arteries were dilated andatherosclerosis was also observed.

gioendothelial cells and the smooth muscle in the thicktunica intima, forming a retiform structure. Concrete
causes have not yet been identiﬁed, but necrotizing
vasculitis has recently been believed to be responsible.
Both lungs weighed 380 g, showing a slight increase
in weight. Macroscopic observation of the cut surface
revealed that the pulmonary artery was dilated, andatherosclerosis was also observed (Fig. 6), secondary to
pulmonary hypertension. The whole cut surface of thelung was slightly more reddish and brownish, reﬂecting
hemorrhage and hemosiderosis.
Microscopic ﬁndings of the lungs are shown in Fig.
7A. Small arteries (100–200 mm in diameter), branching
off from the pulmonary artery, show ﬁbrous thickeningof the tunica intima. There is a reticular slit-like orcapillary-like space in the periphery. This is a plexiform
lesion. In further peripheral areas, dilated blood vessels
ﬁlled with erythrocytes are observed. In this region, thearterial wall has become thin like that of a vein.
EVG staining facilitates identiﬁcation of ﬁbrousthickening of the tunica intima of small arteries andplexiform lesions in the periphery (Fig. 7B). Theselesions are characteristic of PPH and pulmonary hypertension accompanying congenital heart disease.
The pulmonary arteries around the lesions weredilated, and marked hemosiderosis was present in theparenchyma surrounding the pulmonary arteries. Someareas were hemorrhagic, and are considered to haveresulted from hemorrhage from the dilated blood vessels.
Macroscopic observation of the heart showed thatthe right ventricular wall was about 7 mm in thickness(Fig. 8), showing marked thickening, and the right ventricle also showed luminal dilatation. The tricuspid
valve and right atrium were also markedly dilated.
At the site where the ASD had been closed, the following were conﬁrmed: The defect had been sutured in
at least two points; it appeared to be closed but had avalvular form, and the left and right atria communicated with each other. However, the shape looked like

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Satoh T, et al: Pulmonary hypertension patient

Fig. 8 Macroscopic observation of the right heart. The right ventricle
was hypertrophied and dilated.

Fig. 7 Microscopinc ﬁndings of the lung. Fibrous thickening of
the tunica intima of a small artery, plexiform lesion, and dilated thinwalled arteries were observed. A) (H.E.) B) (Elastica van Gieson)that observed in patent foramen ovale; when left atrial
pressure was higher than right atrial pressure, there
was no blood ﬂow, while there was blood ﬂow whenright atrial pressure was higher than left atrial pressure.
Therefore this slit-like communication between the left
and right atria was not considered to be the cause of
pulmonary hypertension.
The liver was a brownish color overall, with sites ofmarked hemorrhage and ﬁndings of chronic and acutecongestion. Microscopically, hepatocytes were relatively preserved around portal areas, but erythrocyte
pooling was observed in ‘‘zone 3’’. The hepatocytes

had mostly dropped out. Along with the chronic courseof congestion, hepatocytes dropped out, and ﬁbrosis
was further associated with the congestion. The pathological ﬁndings conﬁrmed hepatic congestion accompanying right heart failure.
There were hyperplastic nodules of 12 mm and 6
mm diameter in the left lobe of the liver, with a highpossibility of their being focal nodular hyperplasia-likelesions, the presence of which is considered attributable
to localized abnormality of blood ﬂow in the noncirrhotic liver. This type of lesion is characterized by
the presence of ﬁbrous cicatrices and abnormal bloodvessels and has been incidentally detected on autopsy inmany cases, though the frequency is believed to be low.
Recently, however, the detection frequency of theselesions has been increasing owing to advances in diagnostic imaging.
Fig. 9 shows the microscopic ﬁndings of the nodulein the present patient. The liver with changes due tocongestion is seen on the left, and a nodular lesion isshown on the right. Nodular hyperplasia of hepatocytes
is observed, and they have lost their normal lobular
structure, with trabecular proliferation. Large bloodvessels are observed disproportionately at various sites.
The hepatocytic atypia is not the type associated with
hepatocellular carcinoma, but hyperplastic proliferationof hepatocytes may be observed. The lesion is considered to be similar to focal nodular hyperplasia.
Here we can see the pathological ﬁndings in thelungs, which are typical of pulmonary hypertension.

Keio J Med 2003; 52 (4): 250–262

Fig. 9 Microscopic ﬁndings of a hyperplastic nodule of the liver.
Hyperplastic hepatocytes proliferated in trabecular pattern.

They showed plexogenic pulmonary arteriopathy that
corresponded to PPH or pulmonary hypertension associated with congenital heart disease. Lesions accompanying plexogenic pulmonary arteriopathy, which included cor pulmonale and hepatic congestion, wereobserved, and it is considered that the patient died fromright heart failure associated with pulmonary hypertension.
Dr. Kato: How severe was the ﬁbrosis of the liver?
Dr. Okita: The ﬁbrosis was mild to moderate, andinvolved the central area of the lobules, although bridging ﬁbrosis was not yet present.
Dr. Kato: Was hemorrhagic necrosis seen?
Dr. Okita: Hepatocytes gradually dropped out because of chronic congestion, resulting in zonal necrosis.
Zone 3 showed zonal necrosis accompanied by chronic
and acute congestion.
Dr. Kato: Were any necrotic cells detected?
Dr. Okita: The amount of recent necrosis was notlarge.
Dr. Satoh: Prostacyclin was administered to this patient. This drug is considered to reverse hypertrophyof pulmonary arteries. Did you detect any evidence ofreversed remodeling such as relatively reduced medial
or intimal hypertrophy or fewer plexiform lesions which
are indicators of severe pulmonary hypertension?
Dr. Okita: I think it is hard to quantify any suchﬁndings, because the relation between the patient’s status and the following conditions: histopathological severity of the plexiform lesion, symptoms of pulmonary
hypertension, level of pulmonary arterial pressure, andseverity of right heart failure remains unknown. Neither was there any histopathological description concerning lesions with restoration of a thick tunica intima

261

or tunica media. Therefore, it is difﬁcult to evaluate any
such ﬁndings possibly associated with beneﬁcial effects
of prostacyclin.
Dr. Satoh: Did you notice more recanalization of thepulmonary capillaries than usual?
Dr. Okita: There was no particular impression of anincreased frequency of recanalization.
Dr. Satoh: You consider that the pathological ﬁndings in this patient who used prostacyclin were not different from those in patients without prostacyclin administration?
Dr. Okita: Certainly, the following aspects revealed
no particular difference from the usual ﬁndings in PPH:
vasoconstriction was present, plexiform lesions had
formed, and dilated blood vessels were also present.
However, what I did ﬁnd unusual in the present casewere the marked hemorrhage and hemosiderin deposition.
Dr. Satoh: I understand. Any other questions?
Dr. Yagi: This patient had very severe ascites. The
blood data also strongly suggested intravascular dehydration. In spite of this, ascites persisted. It is also considered that ascites was diapedetic, but I wonder about
the cause of ascites in the present patient. The pathological ﬁndings of the liver were not very severe. I canthink of some other possibilities; for instance, I wonder
if retention of such a massive amount of ascites occurred because of the hypothyroidism. Since very severe
tricuspid regurgitation is associated with PPH, hepatic
hypofunction with low output should also be considered.
Dr. Kato: I think the ascites cannot be explained byliver cirrhosis. Marked congestion of the liver and small
intestine is considered to have been present. I wonder
what the ﬁndings in the small intestine were; for instance, I wonder if severe edema or hemorrhage fromthe small intestinal mucosa was present. It is my interpretation that the ascites was secondary to congestion.
Dr. Yagi: In this case, ﬁnally, the amount of retained
ascites may have reached about 5000 ml, but despite
this amount, there was still a tendency toward intravascular dehydration. I wonder if the presence of alarge amount of ascites can be explained only by congestion. I think there was another cause of the occurrence of ascites, related to the liver or abdominalorgans, without edema of the legs.
Dr. Kato: Such a possibility varies on a patient-bypatient basis. As for ascites and edema due to livercirrhosis, the main symptom is ascites in some patients while edema of the legs becomes severe in other
patients. There also may be asymmetry of leg edema. It
is impossible from the ﬁndings alone to rule out livercongestion as being responsible for the ascites, but inmy opinion, congestion of the small intestine in thiscase was strongly related to the ascites.

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Dr. Okita: With regard to the liver, it was muchheavier than usual at 1830 g, indicating very severecongestion. As for ﬁndings in the small intestine, noorganic lesion could be identiﬁed.
Dr. Kato: Occasionally, some reports have shownthat portal hypertension is associated with nodular
hyperplasia. Was there any ﬁnding indicating the presence of varices, for example?

Satoh T, et al: Pulmonary hypertension patientDr. Okita: I don’t think that there was any ﬁnding indicating distinct portal hypertension. The spleen
weighed 150 g, and slight congestion appeared to havebeen present, but not to a great extent. There was no
dilatation of the portal vein or distinct varix.
Dr. Satoh: Are there any other questions? If not, I
would like to conclude this CPC. Thank you for yourattendance and contributions.