Pulmonary Hypertension in Gaucher Disease: The combination of ERT

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The combination of ERT, vasodilators, and coumadin improves the symptoms.

Pramod K. Mistry, MD, PhD
Associate Professor of Internal Medicine and Human Genetics, Director of the National Gaucher Disease Program, Yale School of Medicine, New Haven, CT

Since its introduction more than a decade ago, enzyme replacement therapy (ERT) with Cerezyme® (imiglucerase for injection) has drastically altered the outlook for patients with Gaucher disease. Now considered the standard of care, this therapy alleviates many of the debilitating symptoms involving multiple organ systems that patients with Gaucher disease formerly lived with and, all too often, died from.

The first Gaucher Registry at the University of Pittsburgh in 1981 revealed that patients with Gaucher disease were dying prematurely due to:

• Bleeding complications
• Liver failure
• Complications of crippling bone disease
• Cancer
• Pulmonary hypertension (PH)

These complications were made worse, it was discovered, by splenectomy, a procedure commonly performed on patients with Gaucher disease to alleviate low blood counts and pressure symptoms. Fortunately, splenectomy is no longer necessary, and enzyme replacement therapy can reverse many of the symptoms of Gaucher disease, such as liver/spleen enlargement, bleeding tendency, marrow infiltration, low blood counts, and growth failure in children. In addition, bone crises have been virtually eliminated in these patients. Yet researchers still do not fully understand the effects of ERT on the lungs or the pattern and frequency of lung involvement.

Gaucher Disease’s Effect on the Lungs

Because the lungs are an important site for accumulation of fat-filled cells, it is surprising that patients do not complain more often of lung symptoms. Yet patients with Gaucher disease are known to have broad patterns of lung involvement: in Type 2 Gaucher disease, the Gaucher cells fill the air spaces, causing pneumonia and breathing difficulties; in patients with Type 3 Gaucher disease, the fat-filled cells accumulate in the lung tissue, causing scarring and stiff lungs that lead to shortness of breath; and in those with Type 1 Gaucher disease, the Gaucher cells line small blood vessels, obstructing the flow of blood.

Autopsy studies from many years ago show that some patients had uncontrolled growth of cells lining blood vessels in the lungs, leading to progressive obliteration and high blood pressure in lung circulation (pulmonary hypertension). Yet the link between this phenomenon and Gaucher disease and Gaucher cells is not understood.

Pulmonary Hypertension

In patients with pulmonary hypertension, blood pressure in the pulmonary artery rises above normal. It is the pulmonary artery that carries oxygen-poor blood from the right side of the heart to the lungs, where it picks up oxygen and flows to the left side, from where the left ventricle pumps it to the rest of the body. Measured by Doppler echocardiography (ECG), there are three categories of pulmonary artery pressure:

• Normal, in which pressure is less than 35 mm mercury
• Mild, asymptomatic, in which pressure is 35 to 50 mm
• Severe PH, in which pressure is greater than 50 mm

High pressure is generated to overcome resistance to the flow of blood through the lungs, leading to excessive strain on the right side of the heart and, ultimately, heart failure. In the most advanced stages of disease, patients experience an accumulation of fluid in the legs and abdomen and swelling in the liver. Yet it is important to recognize that patients with PH may not have symptoms for a long time, and when they experience symptoms–tiredness is usually the first–they are likely to think they’re just out of condition. Other typical symptoms include shortness of breath, dizziness or fainting, and palpitations.

The first report of fatal PH in a patient with Type 1 Gaucher disease appeared nearly 40 years ago. Since then, about a dozen cases of severe or fatal PH in Type 1 Gaucher disease have appeared in the literature. In 1998, a study published in Lancet by Elstein and colleagues found that 7% of patients with Type 1 Gaucher disease had PH.¹ The researchers concluded that this unexpectedly high frequency was due to a side effect of Cerezyme and recommended that the effected patients stop taking enzyme treatment.

A New Study

A recently published study by Mistry et al² revisits the problem of PH in patients with Type 1 Gaucher disease. The researchers used ECG to screen a large number of patients with Type 1 Gaucher disease (including those on enzyme treatment and those not receiving enzyme treatment). In addition, nine patients with known, severe, life-threatening PH and Type 1 Gaucher disease were examined.

It was discovered that only about 1% of patients with Type 1 Gaucher disease develop severe, potentially life-threatening PH with symptoms. Of the nine patients with the severe form of PH, five presented with severe PH before they had received any enzyme treatment; in the other four patients, PH was discovered while they were on enzyme treatment. Importantly, these patients had taken drug holidays or demonstrated poor compliance with enzyme treatment -– they had evidence of significant residual Gaucher disease activity at the time of evaluation.

The researchers discovered that patients with Type 1 Gaucher disease who developed severe, potentially life-threatening PH were a distinct group characterized by the following:

• All patients with severe PH were splenectomized.
• Women were more likely to be affected than men (PH due to non-Gaucher disease causes is also worse in women).
• If the patient had a sibling with Gaucher disease, the patient also had severe PH.
• These patients had at least one severe Gaucher disease mutation (e.g., one that was not N370S)
• Patients tended to have genetic variation in angiotensin converting enzyme.
• No enzyme treatment or suboptimal enzyme treatment

The study also found that as many as 30% of patients who were not receiving enzyme therapy had mild, asymptomatic PH; only 7.4% of those receiving ERT had this type of PH.

The researchers concluded that Type 1 Gaucher disease leads to a remarkable tendency to develop PH, but it progresses to the severe form in only 1% of people who have the factors listed above. Mild, asymptomatic PH does not invariably lead to severe PH in the vast majority of patients.

Implications

Although splenectomy is almost always essential to the development of severe PH, it alone cannot cause PH. The above-listed factors are also required to develop full expression of the disease. The greater the number of these factors present in a patient, the greater the likelihood of developing severe PH.

This new insight should allow physicians to identify the highest-risk patients, so they can be monitored regularly for the earliest signs of PH. Every patient with Type 1 Gaucher disease should have a baseline ECG, and physicians should pay particular attention to patients who are splenectomized, those who have cirrhosis of the liver, or those who have symptoms suggestive of PH. Occasionally, despite the presence of significant PH, initial tests, including an ECG, are reported to be normal. Therefore, if there is strong suspicion that the patient may have PH, it is important to consult a Gaucher Center. Fortunately, severe PH does not appear to be a phenomenon found among pediatric Type 1 Gaucher disease patients.

Severe Pulmonary Hypertension

For the 1% of patients with Type 1 Gaucher disease who develop severe PH, this is a life-threatening medical emergency. It requires a meticulous evaluation and treatment by a team of physicians who understand both Gaucher disease and PH. Attention to every detail is required on a daily basis, because these patients can deteriorate with alarming rapidity if their circulatory systems come under stress from any other cause (e.g., infection or pregnancy). To prevent sudden death, all aspects of the disease must be evaluated and treated aggressively.

Without treatment, severe PH progresses rapidly, and patients only survive two to three years, on average. This form of PH in patients with Type 1 Gaucher disease is due to a combination of Gaucher cells plugging blood vessels in the lungs as well as uncontrolled growth of cells lining the blood vessels (endothelial and smooth muscle cells). Treatment should therefore aim to control the patient’s Gaucher disease with ERT as well as arrest uncontrolled growth of cells in the blood vessels. For the latter, coumadin and vasodilators (drugs that reverse blood vessel spasm in the lungs) are the standard of care. The most effective vasodilator therapy until recently was continuous intravenous infusion of Flolan, but several oral alternatives (e.g., tacleer, low-dose Viagra) and an inhaled version of Flolan are now available. In addition, women with severe PH should avoid pregnancy, because changes in circulation can cause catastrophic worsening of PH. Infections should be treated promptly, and any type of surgery in patients with severe PH should be approached with extreme care.

This new study demonstrates that the combination of ERT, vasodilators, and coumadin significantly improves the symptoms and survival rates of patients with Gaucher disease and severe PH.

Additional Research

Further research is now being conducted in an effort to understand the genetic basis of Type 1 Gaucher disease that exhibits severe PH. We are also studying the effects of new vasodilators in severely affected patients. For additional information about these research projects and other Gaucher disease-related studies, contact Luisa Coraluzzi, Research Coordinator, National Gaucher Disease Program, Yale School of Medicine, at (203) 785-4795 or visit http://gaucher.yale.edu.

References

1. Elstein D, Klutstein MW, Lahad A, et al. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet 1998;23(351):1544-6

2. Mistry PK, Sirrs S, Chan A, et al. Pulmonary hypertension type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy. Molecular Genetics and Metabolism 2002;77:91-8.

© 2003 Hybrid Publishing, Inc.

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