A case of pulmonary arterial hypertension with chronic hepatitis that resulted in hepatosplenomegaly after administration of prostaglandin I2

Abstract

The prognosis of pulmonary arterial hypertension (PAH) has significantly improved over the past two decades due to advances in medications, including pulmonary vasodilators. However, the side effects of these drugs remain problematic in some patients. A 51-year-old woman with chronic hepatitis C was diagnosed with PAH 7 years before presenting to our hospital. She was unable to continue her treatment with pulmonary vasodilators due to various side effects. She had a World Health Organization functional class of IV and was started on continuous infusion of prostaglandin I2 (PGI2). This therapy improved her symptoms, including dyspnea and fatigue. However, she began to complain of abdominal distension after 4 months of PGI2 therapy. Computed tomography showed significant hepatosplenomegaly. Her abdominal distension improved slightly after decreasing PGI2 treatment, but her dyspnea on exertion was exacerbated. She died 12 years after diagnosis of PAH due to uncontrollable heart failure. Here, we describe a rare case of PAH with hepatosplenomegaly after administration of PGI2.

<Learning objective: Intravenous continuous prostaglandin (PG) I2 therapy is useful for the treatment of severe pulmonary arterial hypertension (PAH). However, it has numerous side effects that are difficult to control. We report a rare case of PAH with chronic hepatitis C that resulted in hepatosplenomegaly after PGI2 administration. In cases of chronic liver disease, it is important to keep in mind that administration of PGI2 may result in hepatosplenomegaly.>

Introduction

In recent years, many new vasodilators have become available for the treatment of pulmonary arterial hypertension (PAH), and the prognosis of PAH has improved [1]. Intravenous continuous prostaglandin I2 (PGI2) therapy is effective for PAH patients, but its use is limited due to side effects that have an impact on health-related quality of life [2]. We report a rare case of PAH in which hepatosplenomegaly occurred after intravenous continuous PGI2 therapy.

Case report

A 51-year-old woman was admitted to our hospital for the initiation of intravenous continuous PGI2 therapy. She had been diagnosed with PAH 7 years previously, and had been treated with oral administration of pulmonary vasodilators, such as beraprost, sildenafil, bosentan, and ambrisentan. However, it was difficult for her to continue with these medications due to their side effects. Her family history was unremarkable. She did not take any supplements or drugs that could induce pulmonary hypertension.

On admission, her heart rate was 75 bpm, her blood pressure was 96/42 mmHg, and her oxygen saturation on 4 L oxygen was 90%. She was in World Health Organization (WHO) functional class (FC) IV. On auscultation, acceleration of S2 and a holosystolic murmur at the third left sternal border were audible. No rales were heard over the lungs. No leg edema was observed.

Laboratory tests revealed polycythemia, mild renal dysfunction, and a brain natriuretic peptide (BNP) level of 1010 pg/mL (Table 1). In addition, slight liver dysfunction was observed and the patient tested positive for hepatitis C virus (HCV) antibody. The patient was human immunodeficiency virus negative and there were no abnormalities in collagen disease markers. Arterial blood gas analysis showed hypoxemia and respiratory compensation. Chest radiographs showed expansion of the main pulmonary artery, a cardiothoracic ratio of 66%, no pleural effusion, and no pulmonary congestion (Fig. 1A). An electrocardiogram showed a pulmonary P wave, right axis deviation, and right ventricular hypertrophy (Fig. 1B). Echocardiography showed flattening of the left ventricular septum, right ventricular dysfunction, and expansion of the inferior vena cava, and the tricuspid regurgitation pressure gradient (TRPG) was 106 mmHg (Fig. 1C). Left ventricular contractility was preserved, no significant aortic valve or mitral regurgitation was observed, and no pericardial effusion was seen. A respiratory function test showed a normal vital capacity, but forced expiratory volume in 1 s of predicted value (%FEV 1), diffusing capacity of the lung for carbon monoxide (DLCO), and DLCO/alveolar volume (DLCO/VA) were decreased (%FEV 1 58.8 %, DLCO 36.9 mL/min/mmHg, DLCO/VA 45.1 mL/min/mmHg/L). Computed tomography (CT) showed a dilated pulmonary artery, but there was no pulmonary emphysema or interstitial pneumonia. In addition, no hepatosplenomegaly, liver tumor, or biliary tract disease were observed. On abdominal echocardiography, the liver was smooth, sharp, and uniform. A slight swelling of the left lobe was observed, but there was no swelling of the right or caudate lobes. An echo Doppler detected no portal backflow, suggesting the presence of a port-systemic shunt. According to a ventilation-perfusion lung scan, there was no mismatch region.

Table 1.

Blood test parameters showed mild liver and kidney disorders. Arterial blood gas analysis showed hypoxemia and respiratory compensation. After initiation of prostaglandin I2 (PGI2) therapy, a brain natriuretic peptide (BNP) and creatinine levels decreased with improved hemodynamic status, while liver dysfunction worsened.

Parameter	Units	Measurement		Normal reference interval
		Baseline	After
WBC	×103/μl	8.55	7.42	3.3–8.8
RBC	106/μl	5.84	4.16	3.7–4.9
Hb	g/dl	16.9	10.5	11.2–14.5
Plt	103/μl	223	182	130–350
PT-activity	%	73	74	87–131
D-dimer	μg/ml	0.6	0.6	<1
T-Bil	mg/dl	1.1	0.9	0.3–1.2
ALP	IU/l	383	372	115–359
AST	IU/l	37	120	13–33
ALT	IU/l	30	107	6.0–27
Alb	g/dl	5	4.8	4.0–5.0
BUN	mg/dl	45	20	8.0–22
Cre	mg/dl	1.35	0.91	0.50–0.80
BNP	pg/ml	1010	88	<18.4
Arterial pH		7.413	7.52	7.35–7.45
PaO2	mmHg	71.8	83.8	83–108
PaCO2	mmHg	31.6	29.6	32–45
Arterial HCO3−	mmol/l	19.7	23.8	21–28

Fig. 1.

Chest radiographs showed expansion of the main pulmonary artery and an increase in the cardiothoracic ratio (A). Electrocardiography showed pulmonary P wave, right axis deviation, and right ventricular hypertrophy (B). Echocardiography showed flattening of the left ventricular septum in the diastolic phase (C).

In coronary angiography, no stenosis lesions were observed. Right heart catheterization showed obvious right heart load findings, with a mean pulmonary artery pressure (mPAP) of 73 mmHg, a pulmonary vascular resistance (PVR) value of 19.2 wood, and a cardiac index (CI) of 2.06 L/min/m². Wedged hepatic venous pressure (WHVP) was within the normal range. Based on these results, a diagnosis of WHO FC IV PAH with low cardiac output was made. Infusion of PGI2 was started at a low dose (0.25 ng/kg/min) under treatment with dobutamine, and the dose was carefully increased daily by 0.5 ng/kg/min. When the dose of epoprostenol exceeded 10 ng/kg/min, it was increased by 2 ng/kg/min every week, and reached 34.4 ng/kg/min in 3 months. After initiation of PGI2 therapy, the patient’s shortness of breath improved to WHO FC III. On right heart catheterization, the patient’s mPAP was 39 mmHg, her PVR was 10.9 wood, and her CI was 2.93 L/min/m². Echocardiography showed a decrease in diameter of the inferior vena cava and the TRPG was 36 mmHg. Hemodynamic parameters were significantly improved and there were no signs of exacerbated right heart failure or venous congestion. However, she complained of abdominal fullness, diarrhea, and nasal bleeding after 4 months of treatment with PGI2. In an abdominal echo scan, hepatosplenomegaly and ascites were observed, and a CT of the abdomen showed marked hepatomegaly with a volume of 2337 cm² as well as splenomegaly (Fig. 2A–D). There were no obstructions in the hepatic vein suggestive of Budd-Chiari syndrome (BCS). Anemia and thrombocytopenia were observed. According to right heart catheter examinations, the WHVP had increased to 16 mmHg and the hepatic venous pressure gradient (HVPG) had increased to 12 mmHg. Liver biopsy showed that the portal region had fibrous enlargement, and there was mild inflammatory cell infiltration mainly in the portal region and the parenchyma. In addition, congestion, fibrosis, and hepatocellular loss were observed around the central vein (Fig. 2E). The PGI2 was reduced (27 ng/kg/min) because the patient’s abdominal distension had worsened. When the PGI2 was reduced, the abdominal distension and hepatic dysfunction improved slightly, but the hepatosplenomegaly remained. Thereafter, the patient’s symptoms of abdominal fullness gradually worsened. Instead of further decreasing PGI2 treatment, riociguat, tadalafil, and macitentan treatment were attempted, but side effects including rash, itching, and swelling of the lip occurred and these medications were discontinued. The patient died 12 years after diagnosis of PAH because of uncontrollable heart failure. A pathological autopsy was not performed at the request of her family.

Fig. 2.

Computed tomography showed significant hepatosplenomegaly. The hepatosplenomegaly was worse after administration of prostaglandin I2 (PGI2) (B, D) compared to before administration of PGI2 (A, C). A liver section stained with hematoxylin-eosin showed fibrous enlargement in the portal region, and mild inflammatory cell infiltration was detected mainly in the portal region and parenchyma. In addition, congestion, fibrosis, and hepatocellular loss were observed in the central leaflet (E).

Discussion

Here, we report a rare case of PAH with hepatosplenomegaly after PGI2 administration. The diagnosis of PAH was confirmed by normal perfusion scan findings and the presence of pre-capillary pulmonary hypertension on right heart catheterization. Although her test of HCV antibody was positive, she had neither clinical signs of liver cirrhosis nor portal hypertension on abdominal Doppler ultrasonography. Chest CT did not show signs of emphysema or interstitial pneumonia. Based on these results, we diagnosed the patient with PAH and started intravenous PGI2 therapy.

Treatment with continuous intravenous PGI2 has been shown to improve life expectancy, 6-min walk test results, and quality of life in patients with severe WHO class III and IV PAH. Increasing the dose of PGI2 is critical for its effectiveness, but it can also increase the occurrence and intensity of side effects, which may result in treatment discontinuation. Side effects of PGI2 therapy include jaw pain, diarrhea, erythema, arthralgia, headache, and pulmonary edema [2]. Findlay et al. [3] reported four cases of portopulmonary hypertension showing progressive splenomegaly with worsening thrombocytopenia and leukopenia after treatment with epoprostenol. However, hepatosplenomegaly has not been reported as a side effect of PGI2 for patients with PAH. This is the first report of hepatosplenomegaly after administration of PGI2 in a PAH patient without portal hypertension.

After initiation of PGI2 treatment, the liver and spleen were enlarged and the HVPG had also increased. The HVPG measurement has been used for diagnosis of fibrosis, risk stratification, and to assess the prognosis of liver fibrosis [4]. According to the classification of chronic liver disease, our patient with an HVPG of 12 mmHg had cirrhotic stage disease (METAVIR F4) [5]. However, liver biopsy results indicated mild fibrosis and lymphoid aggregation in the portal vein, which were attributed to chronic hepatitis C, and were considered to reflect fibrosis at the F2 level and inflammation at the A1–2 levels. There was no fibrous obliteration of central vein branches or surrounding centrizonal perisinusoidal fibrosis to suggest BCS. These results suggest that the increase in HVPG was due to a mechanism other than liver fibrosis.

PGI2, an IP receptor activator, stimulates the IP receptor expressed on vascular smooth muscle cells, increases vasorelaxation, and suppresses proliferation of vascular smooth muscle cells [6]. PGI2 activates G proteins coupled to the IP receptor to increase cAMP, which in turn activates the catalytic activity of protein kinase A [7]. IP receptors are expressed in the vascular tissue of various organs, such as the aorta, coronary arteries, and pulmonary arteries, and are confined to smooth muscle cells. Importantly, these receptors are not expressed in veins [8]. These results suggest that exogenous PGI2 can induce dilation of the hepatic artery and further increase blood inflow. However, portal hypertension and hepatosplenomegaly are rare side effects of PGI2 therapy despite increased blood flow. In our case, fibrosis around the central vein caused by congestive heart failure and repeated drug-induced liver injury may have impaired hepatic blood outflow and resulted in hepatosplenomegaly. In addition, the patient’s hepatomegaly might have progressed easily because her liver was not as hard as in cirrhosis.

As mentioned above, the patient received delayed therapeutic intervention due to the side effects of multiple drugs for PAH, which led to a poor prognosis. Through this case, we reconfirmed the importance of early intervention for PAH and the development of novel therapeutic drugs with different underlying mechanisms.

In summary, we report a rare case of PAH with chronic hepatitis in a patient who developed hepatosplenomegaly after initiation of PGI2 therapy. PGI2 should be administered very carefully in patients with PAH who have chronic liver disease, even in cases without portal hypertension.

Conflict of interest

The author(s) declare no conflicts of interest.