Portopulmonary hypertension is a rare complication of portal hypertension. Although epoprostenol infusion, nitric oxide inhalation, isosorbide-5-mononitrate, nitroglycerin, and calcium channel blockers may reduce pulmonary artery pressure in patients with portopulmonary hypertension, the prognosis remains poor. We present a case of congenital hepatic fibrosis associated with pulmonary hypertension. A 42-year-old man with congenital hepatic fibrosis visited our hospital with syncope. The man had suffered from breathlessness on exertion for 2 weeks before the episode of syncope. He also had a history of portal hypertension with documented gastric cardiac varices at the age of 28 years. Despite undergoing intensive care, the patient died 1 week after admission owing to severe right-sided heart failure. Autopsy revealed dilatation of the right atrium and right ventricle grossly and plexogenic pulmonary arteriopathy microscopically. Accurate diagnosis of portopulmonary hypertension requires awareness of the disease and a high index of suspicion when examining patients with portal hypertension and dyspnea. (Chang Gung Med J 2003;26:193-8)

Key words:
congenital hepatic fibrosis, pulmonary hypertension, portal hypertension, plexogenic pulmonary arteriopathy.

CASE REPORT

A 42-year-old man with a history of congenital hepatic fibrosis visited our emergency department (ED) due to syncope on July 27, 1993.
The patient underwent splenectomy for splenomegaly related variceal bleeding on admission to another hospital in 1963 when he was 12 years old. The patient was later admitted to our hospital in November 1979 complaining of right upper quadrant pain and fever lasting for 4 days. Laparotomy found a distended and edematous gallbladder with no common bile duct dilatation or gallstones. Cholecystectomy was also performed, and an endoscope examination found mild gastric cardiac varices. An accidental explosion related penetration injury to the chest and right hemopneumothorax occurred in September 1988. During hospitalization for this injury, the patient received an endoscopic examination that revealed progression of the esophageal and gastric cardiac varices. Tests for hepatitis B surface antigen and hepatitis C antibody were all negative.
The patient remained symptom free until 2 weeks before his final admission, at which point he began to experience breathlessness on exertion. No orthopnea, paroxysmal nocturnal dyspnea or leg edema occurred. The patient denied having experienced fever, chills, night sweating, or productive cough. The patient was finally sent to our ED after he was found lying unconscious in the toilet. He regained consciousness on the way to hospital. Hypotension was detected at our ED.
Physical examination revealed that the body temperature was 37oC, pulse rate was 108/min, and respiration rate was 24/min. The head was normal besides mildly icteric sclera. Meanwhile, the central vein pressure was 29 cm. The heartbeat was regular but auscultation detected a grade 2/6 systolic murmur of tricuspid regurgitation. No crackles were found over the lung fields. The liver was firm with a blunt margin, and its span was 13 cm at the right middle clavicle line. Collateral circulation was present on the abdominal wall but percussion did not reveal shifting dullness. No cyanosis, Roth spot, Janeway's lesion, or Osler's node was present. Neurological examination was essentially normal.
Liver function test revealed that aspartate aminotransferase was 76 U/l, alanine aminotransferase was 36 U/l, total bilirubin was 3.0 mg/dl, alkaline phosphatase was 283 U/l (reference range, 28-94 U/l), and g-glutamyltransferase was 178 U/l (reference range, 0-26 U/l). Thrombocytopenia (53000/mm3) and mild normocytic anemia (hemoglobin 11.4 g/dl) were also detected. Prothrombin time was 17.6 seconds with a control of 11.7 seconds. Arterial blood gas displayed respiratory alkalosis (P CO2 23.3 mmHg) and P-aO2 130.4 mmHg when a 50% O2 mask was used. Chest radiograph found a prominent pulmonary trunk and cardiomegaly. Finally, a doppler cardioechographic study revealed features of severe pulmonary hypertension with severe tricuspid and pulmonic regurgitation.
The patient was hypotensive and received fluid resuscitation and oxygen. Apnea, spastic position, and cyanosis occurred on the third day after admission. Persistent hypotension, tachycardia, and tachypnea were noted despite aggressive use of inotropic agents and mechanical ventilation. The patient died on August 2, 1993.
At autopsy, the liver weighed 1620 g and had an undulating surface and a firm consistency. Microscopic examination revealed a diffuse peripheral fibrosis and a jigsaw pattern of the hepatic parenchyma. The irregular shaped islands of the hepatic parenchyma comprised normally arranged hepatocytes with a central vein (Fig. 1A). Multiple small bile ducts were scattered in the fibrous tissue and a few contained bile that was compatible with congenital hepatic fibrosis (Fig. 1B). Varices were noted in the esophagus, stomach, and small intestine. Lung sections revealed multiple plexiform lesions of small arteries without arteriovenous shunting or emphysema (Fig. 2). Furthermore, dilatation of the right atrium and tricuspid valve were noted, as was hypertrophy of the right ventricle (0.8 cm in thickness), both without congenital anomalies. The right and left kidneys weighed 123 g and 134 g respectively, and displayed severe autolysis and congestion with a few small cortical cysts. A small angiomyolipoma was found in the right kidney.
DISCUSSION

The case presented was congenital hepatic fibrosis complicated by portal hypertension and PH. Congenital hepatic fibrosis was thought to result from ductal plate malformation owing to disturbance of the epithelio-mesenchymal inductive interactions.(9) The apparently normal plates of hepatocytes surrounded by extensive broad bands of periportal or perilobular fibrous tissue are characteristic histological patterns of this disease. No nodular regeneration or inflammation accompanies this condition. The disease is often misdiagnosed as cirrhosis. However, the present case did not show evidence of parenchymal destruction or regeneration, thus, it was distinguished from cirrhosis. Clinically four forms of the disease are recognized including the portal hypertensive form, cholangitic form, mixed portal hypertensive-cholangitic form, and latent form.(9) The present case is most likely the portal hypertensive form. In addition, congenital hepatic fibrosis is frequently associated with cystic renal lesions. Indeed, autopsy revealed small cystic lesions in the present case.
The association between portal hypertension and PH has been well documented.(2,6) Primary PH is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or greater than 30 mmHg during exercise with normal pulmonary artery wedge pressure and no identifiable secondary cause.(10) Portal hypertension has been considered a secondary cause of PH in the Pulmonary Hypertension Consensus Statement issued by the American College of Chest Physicians in 1993.(11) The prevalence of PH in populations with portal hypertension with or without liver cirrhosis is 0.61 to 2%.(2,6) The risk of developing PH appears to increase with the duration of portal hypertension but is unrelated to its severity.(6) This phenomenon could explain the higher prevalence of PH among liver transplant patients (3.5 to 8.5%).(12) The causes of non-cirrhotic portopulmonary hypertension include nodular regenerative hyperplasia of the liver, portal vein thrombosis, congenital portal circulation abnormalities, hepatic vein fibrosis, periportal fibrosis, and congenital hepatic fibrosis.(3-8) The literature contains few reports dealing with congenital hepatic fibrosis complicated by PH.(4,5) Portal hypertension generally precedes the diagnosis of PH, but the interval may be as long as 15 years.(7) The mean age when PH was diagnosed was 47 years, compared with 36 years in patients with primary PH.(13)
The most common presenting symptom of portopulmonary hypertension is exertional dyspnea (81%), and other symptoms include syncope, chest pain, fatigue, hemoptysis, and edema.(3,6,13) Sixty percent of patients with portopulmonary hypertension were clinically asymptomatic when PH was detected incidentally by cardiac catheterization.(6) Consequently, clinicians may overlook portopulmonary hypertension in cirrhotic patients owing to its subtle initial symptoms, similar presentation of complications of decompensated liver cirrhosis with portal hypertension, and the physicians' lack of awareness of the disease.
The histological pictures of portopulmonary hypertension are identical to those of primary PH with pulmonary arteriopathy involving the muscular arteries as an isolated medical hypertrophy, plexogenic pulmonary arteriopathy, or thrombotic pulmonary arteriopathy.(13) The mechanism of the relationship between portal hypertension and PH remains unclear. Recurrent microemboli to the pulmonary vessels from the portal veins, hyperdynamic circulatory state, and the presence of vasoactive humoral factors that bypass the sinusoids have all been proposed as possible causes.(7,13) PH may develop from pulmonary endothelial dysfunction in susceptible patients leading to pulmonary arteriopathy.(13)
The management of portopumonary hypertension includes pharmacological measures and organ transplantation. Chronic epoprostenol infusion has been demonstrated to be effective.(14) Furthermore, the combination of nitric oxide inhalation and epoprostenol infusion was successfully used to control PH perioperatively in a patient undergoing liver transplantation.(15) Isosorbide-5-mononitrate, nitroglycerin, and calcium channel blockers have also been reported to reduce pulmonary artery pressure in patients with portopulmonary hypertension.(13,16) There have also been reports that portopulmonary hypertension can improve, persist, or deteriorate after liver transplantation.(12,13,17,18) Nevertheless severe PH has been associated with increased mortality following liver transplantation.(12) Concurrent heart-lung and liver transplantation is a feasible procedure for selected patients with advanced pulmonary and hepatic disease.(19)
The prognosis of portopulmonary hypertension is poor. The mean survival time after diagnosis is 15 months, compared to 2.5 years for patients with other types of primary PH.(20) Therefore, a high index of suspicion is mandatory for patients with portal hypertension exhibiting dyspnea with unknown cause.

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From the Division of Gastroenterology, Department of Internal Medicine, 1Department of Pathology, Chang Gung Memorial Hospital, Taipei.
Received: May 22, 2002
Accepted: Jul. 25, 2002
Address for reprints: Dr Cheng-Tang Chiu, Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital. 5, Fushing Street, Gueishan Shiang, Taoyuan, Taiwan 333, R.O.C.
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