Case No. 1
GB was a 35-year-old white male who initially presented with lower extremity edema and weakness and was found to have end-stage liver disease due to HCV and alcohol abuse. Over the next several months, he developed decompensated liver disease with ascites. His past medical history was significant for a cholecystectomy for gallstones. His family history was significant for a mother who died of lung cancer and a father with coronary artery disease. He started drinking excessively at the age of 16 and occasionally used other illegal drugs, including amphetamines, heroin, and intranasal cocaine. He abstained from drug and alcohol use from the time of his initial presentation.
Physical examination was significant for a nontender but distended abdomen. The liver edge was 3 cm below the costal margin and a palpable spleen tip was present. Shifting dullness was present and pedal edema was noted to the level of the knees. The lungs were clear bilaterally. Cardiac examination revealed a normal rate and rhythm with no murmurs or gallop sounds.
Initial laboratory evaluation revealed normal electrolytes, normal renal function, and a prothrombin time of 15.8 s (normal 10.8–12.8 s). Serum aminotransferase levels (AST/ALT) were 226/183 IU/L, with a normal alkaline phosphatase and total bilirubin level. The serum albumin level was 3.3 mg/dl. A complete blood count documented a platelet count of 89,000/mm3. Serum tests were positive for HCV-RNA genotype 1a infection with a viral load > 1 × 106 copies/mL.
An abdominal computed tomography scan revealed a nodular cirrhotic liver with a volume of 1,600 cm3. The presence of prominent perigastric varices and periumbilical collaterals consistent with portal hypertension were noted also. Abdominal ultrasound documented the liver to have increased echogenicity. The portal and hepatic veins as well as the hepatic arteries were patent. A echocardiogram documented a left ventricular ejection fraction of 60% with normal heart valves and a normal estimated pulmonary artery pressure (PAP).
A liver biopsy was obtained and interpreted as showing grade 4, stage 4 disease. He was started on IFNα 3 million units daily in May 1999 in an effort to clear his viremia prior to transplantation. His viral load rapidly decreased and became undetectable at 8 weeks. He underwent orthotopic liver transplant 6 months later.
Postoperatively, he was found to have recurrent HCV with a viral load of 8.5 × 105 copies/mL. He was started on cIFN at a dose of 15 ug/day. He again responded rapidly and was HCV polymerase chain reaction (PCR)-negative by 8 weeks. His only complaint during the treatment period was persistent fatigue, which was attributed to the IFNα therapy.
After approximately 1 year of therapy, he began to experience progressive dyspnea on exertion, fatigue, and edema. An examination at this time revealed a resting tachycardia; a new grade III/VI systolic ejection murmur which increased in intensity with inspiration. He was admitted to hospital for further evaluation and was found to have severe pulmonary hypertension with right heart failure.
Cardiac catheterization revealed PAP of 81/30 mmHg, a cardiac output of 8.33 L/min, pulmonary vascular resistance (PVR) of 8.26 cm H2O/L/min, and a cardiac index of 2.61 L/min/m2. He experienced no change in his symptoms with the use of short-acting vasodilators. A ventilation perfusion scan was reported as having low probability for pulmonary emboli. A diagnosis of pulmonary hypertension of unknown etiology was made. He was classified as NYHC III and was started on bosentan, an endothelin receptor blocker, as well as a calcium channel blocker, a diuretic, and digitalis.
He failed bosentan as well as treprostinil, a prostacyclin analog, but had a minor response to epoprostenol. He required repeated admissions for progressive cardiac decompensation and the development of a persistent right-sided pleural effusion. Ultimately, he died in November 2002. The family refused an autopsy.
Case No. 2
DS was a 40-year-old female who was found to have an HCV infection while attempting to donate blood. Her past medical history included mild asthma, depression, a panic disorder, and multiple orthopedic surgeries related to a motor vehicle accident 20 years earlier, at which time she received 3 units of packed red blood cells. Her only medication was an inhaled bronchodilator. Social history included a 30-pack-year smoking history with occasional alcohol use. No intravenous drug use was reported.
A review of systems was unremarkable. Physical examination revealed clear lungs, and cardiac examination was with regular heart rate and no murmur or gallop. Abdominal examination revealed normal bowel sounds, no tenderness, and no hepatosplenomegaly. No pedal edema was appreciated. Laboratory examination included normal electrolytes, renal function, and liver function tests. The patient was found to have a genotype 1b infection with a viral load of 1.2 × 106 copies/mL. A liver biopsy was obtained and interpreted as showing grade 1 stage 1 disease. Mild steatosis was noted also. An upper gastrointestinal endoscopy was unremarkable. She was started on IFNα therapy (3 million units daily) with ribavirin (800 mg daily). The ribavirin was discontinued after 4 months because of profound anemia (Hgb 4.5 gm/dL). She failed to achieve viral clearance, despite being on maintenance therapy for 32 months.
In February 2001, she reported progressive dyspnea on exertion, edema, and weight gain. This required hospitalization and the IFNα therapy was discontinued. On physical examination, an elevated jugulo-venous pressure was appreciated, the lungs were clear, and cardiac examination revealed a grade 2/6 systolic ejection murmur at the left lower sternal border with a prominent pulmonic second sound that increased with inspiration. Pedal edema was present up to her knees. Neurologic examination was unremarkable.
An EKG showed sinus rhythm with voltage criteria for right ventricular hypertrophy and left atrial enlargement. Her chest X-ray was unremarkable. Pulmonary function studies were consistent with minimal asthma. She had unremarkable arterial blood gas on room air (pH 7.42, pO2 102, pCO2 33). A cardiac echocardiogram demonstrated normal left ventricular ejection fraction (59%), diffusely dilated, hypertrophied, and hypokinetic right ventricle, severe tricuspid regurgitation, and a small pericardial effusion without evidence of cardiac tamponade. A ventilation perfusion scan was interpreted as having an intermediate probability of pulmonary embolism. A subsequent pulmonary angiogram revealed no evidence of thromboembolic disease. Right heart catheterization documented a right atrial pressure of 24 mm Hg, right ventricle systolic pressure of 67 mm Hg, right ventricle end diastolic pressure of 11 mm Hg, PAP of 71/34 mm Hg with a mean pulmonary arterial pressure of 52 mm Hg, and pulmonary artery wedge pressure of 24 mm Hg.
Severe pulmonary hypertension with NYHC III heart failure of uncertain etiology was diagnosed. She was started on a diuretic and a calcium channel blocker and experienced a gradual worsening of her symptoms. Subsequently, she was started on treprostinil, with stabilization but no reversal of her pulmonary hypertension.
Case No. 3
FM was a 50-year-old male who presented initially with a pericardial effusion in 1997. At that time, the effusion was drained, with no specific etiology being identified, although he was known to be HCV-positive. Subsequent workup revealed advanced liver disease with decompensated cirrhosis. He underwent liver transplantation soon thereafter. The post-transplant course was uncomplicated, except for recurrent HCV. His past medical history was significant for obstructive sleep apnea, hyperthyroidism, and hypertriglyceridemia. Social history revealed 40-pack-year tobacco use, which he terminated approximately 10 years earlier, and a distant history of alcohol and cocaine use. He was married and worked in a soft drink bottling factory. A review of systems was noncontributory. Physical examination revealed an obese man in no distress. The lungs were clear to auscultation bilaterally and the cardiac examination was unremarkable. The abdomen was protuberant and nontender with palpable hepatosplenomegaly. No ascites was appreciated and he had no edema.
The laboratory data was remarkable for mild renal insufficiency (BUN/Cr 23 mg/dl/1.6 mg/dl) with a platelet count of 105,000/mm3 and a WBC count of 4.1 × 1,000 cells/mm3. Liver function tests were normal and he was found to have an HCV viral load of 2.5 × 105 copies/mL. A liver biopsy showed stage I disease with no portal or lobular inflammation and mild sinusoidal fibrosis.
IFNα therapy (5 million units/day) with ribavirin 200 mg BID was initiated. After being on therapy for 10 months, he developed progressive dyspnea on exertion with pedal edema. The patient was admitted to hospital and the IFNα and ribavirin were discontinued. Physical examination showed him to have clear lungs, and a cardiac examination revealed an early systolic murmur with a prominent pulmonic second sound. The abdomen was protuberant with easily palpable hepatomegaly and normoactive bowel sounds. Mild lower extremity edema was noted.
His evaluation included pulmonary function testing, which showed a significant restrictive defect with dramatic reduction in diffusion capacity. Computed tomography of the abdomen showed massive hepatomegaly (liver volume 3,448 cc3), splenomegaly, and ascites. A ventilation perfusion scan was negative for thromboembolic disease. An echocardiogram documented severe left ventricular hypertrophy, enlargement of the right heart chambers with severe tricuspid regurgitation, and an elevated PAP (80 mm Hg). A diagnosis of severe pulmonary hypertension with resultant cor pulmonale was made. The IFN therapy was discontinued and treatment was initiated with a diuretic and a calcium channel blocker with stabilization, but there was no improvement in his pulmonary hypertension.
Case No. 4
DM was a 49-year-old male who was noted to have elevated serum aminotransferase levels (AST/ALT 228/136 IU/L). Workup revealed chronic HCV infection. He was in good health and had no specific complaints. His past medical history was unremarkable. He had no allergies and was on no medications. Social history revealed a 40-pack-year tobacco history and occasional use of alcohol. He denied any intravenous drug use. Family history was negative. A review of systems was positive only for generalized malaise. Physical examination revealed clear lungs, cardiac examination with no murmurs, the abdomen was soft with a liver and a spleen palpable 3–4 finger breadths below the costal margins. No peripheral edema was present.
Laboratory evaluation revealed normal electrolytes and renal function. Complete blood count showed WBC 2.8 × 1,000 cells/mm3 and a platelet count of 80,000/mm3. Liver function tests documented serum aminotransferase elevations with a normal bilirubin level. HCV genotype 1 was found with a viral load of 1.8 × 106 copies.
A computed tomography scan of the abdomen revealed a cirrhotic liver with splenomegaly and evidence of portal hypertension with recanalization of the periumbilical veins. An upper endoscopy revealed grade II esophageal varices with portal hypertensive gastropathy.
He was started on IFNα therapy (PEG-Intron® 2 μg/kg/week) with ribavirin (200 mg BID). Eight months after the initiation of therapy, the patient developed progressive dyspnea on exertion with increasing abdominal girth and pedal edema. The IFNα and ribavirin therapy were discontinued. Re-evaluation at this time revealed a normal chest X-ray. Pulmonary function tests documented a moderate to severe decrease in diffusion capacity with a mild reversible obstructive ventilatory defect. A cardiac echogram documented normal left ventricular size and function (EF 60%) and a normal right ventricular size. Moderate tricuspid regurgitation was noted, with a markedly elevated PAP of 80 mm Hg. A ventilation perfusion scan was negative for thromboembolic disease. The patient was diagnosed as having severe pulmonary hypertension of unknown etiology and was treated with a diuretic and calcium channel blocker with good results. He remains clinically stable however, without improvement in his pulmonary hypertension.