Pulmonary Hypertension In Gaucher Disease by Pramod K Mistry

Pramod K Mistry MD, PhD,

National Gaucher Disease Program

Yale

School

of

Medicine

,

New Haven

,

Connecticut

The current status of severe PH in type 1 Gaucher disease reflects extra-ordinary achievements of enzyme therapy after its introduction only a decade ago. When ERT was not available, development of severe PH was a terminal event. The era of ERT has ushered in a new phase in understanding this phenomenon and its treatment. It seems highly likely that the new generation of patients who receive the standard of care treatment for type 1 Gaucher disease will not develop this most feared complication, representing yet another milestone in conquering the ravages of this disease.

Before the discovery of successful enzyme replacement therapy by Dr Roscoe Brady and his associates about a decade ago, the overall outlook in type 1 Gaucher disease was extremely poor since patients suffered from many years of debilitating symptoms involving multiple organ systems. In addition, data compiled from the first Gaucher Registry at University of Pittsburgh in 1981, showed that patients with type 1 Gaucher disease suffered pre-mature demise due to bleeding complications, liver failure, complications of crippling bone disease, cancer and pulmonary hypertension. Tragically, splenectomy, commonly performed to alleviate low blood counts and pressure symptoms led to worsening of all of these complications.

Enzyme replacement therapy (ERT) with Cerezyme has dramatically improved the health of Gaucher patients and it is now the standard of care for people with type 1 Gaucher disease. For example, liver/spleen enlargement, bleeding tendency, marrow infiltration, low blood counts and growth failure in children can be effectively reversed. Occurrence of bone crises has been virtually eliminated. Importantly, it is no longer necessary to perform splenectomy which aggravated many of the complications described above. Despite these advances, the effects of ERT on the lungs is not well understood, nor is the pattern and frequency of lung involvement.

How does GD affect the lungs?

The lungs are an important site for accumulation of fat-filled cells (Gaucher cells) in Gaucher disease. Therefore, it is surprising that patients do not complain more often of lung symptoms. Nevertheless, three broad patterns of lung involvement are recognized with some overlap. In type 2 Gaucher disease, the Gaucher cells fill the air spaces causing pneumonia and breathing difficulties. In type 3 Gaucher disease, the fat filled cells accumulate in the lung tissue causing scarring and stiff lungs that lead to shortness of breath. In type 1 Gaucher disease, the Gaucher cells line small blood vessel obstructing the flow of blood. We also know from autopsy studies reported many years ago that in some patients, there is uncontrolled growth of cells lining blood vessels in the lungs that cause progressive obliteration and leads to high pressure in lung circulation (pulmonary hypertension); the link between this phenomenon and Gaucher disease or Gaucher cells is not understood.

What is pulmonary hypertension (PH) ?

PH is present when blood pressure in the pulmonary artery rises above normal. The pulmonary artery is the muscular tube that carries oxygen-poor blood from right side of the heart to the lungs where it picks up oxygen and then flows to the left side, from where the left ventricle pumps it the rest of the body. Using Doppler echocardiography (a sonogram of the heart), 3 categories of pulmonary artery pressure are recognized :

Normal

( pressure < 35 mm mercury), mild, asymptomatic ( pressure 35-50 mm) and severe PH (greater than 50 mm ). However the exact definitions vary depending on what technique is used to measure the pressure, for example, echocardiogram or by direct pressure measurement with a catheter in the heart, which is considered the gold standard. High pressure has to be generated to overcome resistance to flow of blood through the lungs (due to narrowing of blood vessels by uncontrolled growth of endothelial cells and smooth muscle cells lining the blood vessel wall, fat-filled Gaucher cells or small blood clots). In time this puts excessive strain on the right side of the heart leading to right heart failure. In right heart failure, there is accumulation of fluid in the legs and abdomen (ascites) as well as swelling of the liver.

It is important to understand that PH can remain occult and asymptomatic (cause no symptoms) for a long time. The first symptom is frequently tiredness, with many people thinking they are simply out of condition. Shortness of breath, dizziness or fainting and racing pulse (palpitations) are also typical symptoms. Symptoms of right heart failure described above occur in the most advanced stages.

It is believed that in people who develop PH, the lung blood vessels are very sensitive and go into a spasm when exposed to certain internal or external stimuli. For example people with Raynaud’s syndrome are more likely than other to develop PH; Raynaud’s is a condition in which fingers and toes go blue on exposure to cold because the blood vessels are very sensitive to temperature. Diet suppressants, AIDS virus, rheumatoid arthritis and related conditions and cirrhosis of the liver are also thought to trigger this type of spasm in the pulmonary artery and therefore these conditions are ‘risk factors’ for developing PH. There is also an inherited form of PH but only 1 in 5 person carrying the defective gene develops PH, indicating that other factors are very important to develop full disease. Severe PH is extremely rare and only a few hundred new cases are diagnosed each year in

USA

.

Pulmonary hypertension and type 1 Gaucher disease

It was nearly 4 decades ago that the first report appeared of fatal PH in type 1 Gaucher disease. Since then about dozen cases of severe or fatal PH in type 1 Gaucher disease have appeared in the literature. In 1998, a study from

Israel

published in the Lancet found that 7% of patients with type 1 GD had PH. These researchers concluded that this unexpectedly high frequency was due to a side-effect of Cerezyme and recommended that affected individuals should stop taking enzyme treatment.

A new study on PH and type 1 Gaucher disease

A new study published this month (

Mistry PK

et al

, Molecular Genetics and Metabolism) revisits the problem of PH in type 1 Gaucher disease. This study involved screening by echocardiogram a large number of patients with type 1 Gaucher disease that included those on enzyme treatment as well as those not receiving enzyme treatment. In addition, 9 patients with known, severe life-threatening PH and type 1 GD were examined in detail to identify unique characteristics of these patients compared to others.

The study found that only ~1% of type 1 Gaucher disease patients develop severe, potentially life-threatening PH with symptoms. Detailed examination of 9 patients with this severe form of PH revealed that 5 of the 9 presented with severe PH before they had received any enzyme treatment and in the other 4, PH was discovered while on enzyme treatment. These 4 patients had taken drug holidays or complied poorly with enzyme treatment such that they had evidence of significant residual Gaucher disease activity at the time of evaluation. The study revealed that type 1 GD patients who developed severe, potentially life-threatening PH were a distinct group characterized by:

• All patients with severe PH are splenectomized (Odds ratio for developing PH in presence of splenectomy was 29, compared to those with intact spleen)
• Women more likely to be affected than men (2:1). This gender difference is interesting since it is known that PH due to non-GD causes is also worse in women.
• If they had a sibling with Gaucher disease, he/she also had severe PH. In other words there was a strong genetic component to this type of GD that exhibits severe PH.
• Had at least one severe Gaucher disease mutation (ie, one that was not N370S)
• Tended to have genetic variation in ACE (angiotensin converting enzyme). ACE is produced in large quantities by Gaucher cells and in fact, we use it as a marker to follow GD. Recent studies have implicated ACE in development of non-GD related PH.
• No enzyme treatment or sub-optimal enzyme treatment

In contrast to the rare occurrence of severe PH described above, the study revealed that as many as 30% of patients not on enzyme therapy had mild, asymptomatic PH and this was reduced to 7.4% among patients receiving enzyme therapy.  This means 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 additional factors listed above. Therefore mild, asymptomatic PH does not invariably lead to severe PH in the vast majority of patients.

What this means to people with type 1 Gaucher disease

Identifying risk factors shown above allows us to construct a ‘profile’ of a type 1 Gaucher disease patient who is most likely to develop severe PH. It is important to understand that while splenectomy is an almost essential requirement to develop severe PH, it is not enough by itself; other factors described above are required to develop full expression of the disease. The greater the number of the above factors present in a single individual, the greater the likelihood of developing severe PH.

This new insight should allow your physician to identify the highest risk patients to monitor regularly for earliest signs of PH. In general, every patient with type 1 Gaucher disease should have a baseline echocardiogram. Particular attention should be paid to those who are splenectomized, those who have cirrhosis of the liver or those who have symptoms suggestive of PH. Occasionally, despite presence of significant PH, initial tests including echocardiogram are reported normal. Therefore, if there is strong suspicion, it is important to consult a

Gaucher

Center

with expertise in this problem. Fortunately, severe PH does not appear to be a phenomenon of pediatric type 1 GD patients and therefore parents of children with type 1 GD should not be overly concerned about this problem.

While the fact that only 1% of type 1 GD patients develop severe PH is good news for the majority, for that 1 severely affected patient (out of 100), this is a life-threatening medical emergency. It requires a most meticulous evaluation and treatment by a team of doctors who understand both Gaucher disease as well as pulmonary hypertension. Every attention to detail is required on a day to day basis, since these patients can deteriorate with alarming rapidity if the circulation comes under stress from any other cause (for example due to infection or pregnancy). All aspects of the disease have to be evaluated and treated aggressively. In this way, sudden tragic deaths can be prevented.

What can be done for a type 1 Gaucher disease patient  with severe PH

Without treatment, severe PH progresses rapidly and average survival is only 2-3 years. Severe PH of 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). Therefore treatment should be targeted to optimal control of Gaucher disease with ERT as well as arresting uncontrolled growth of cells in the blood vessels. For the latter, use of 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 a drug, Flolan but several oral alternatives (ie, tacleer, low dose Viagra) and even inhaled version of Flolan are now available. In addition, women with severe PH should avoid pregnancy since changes in circulation can cause catastrophic worsening of PH. Infections should be treated promptly. Any kind of surgery in people with severe PH should be approached with extreme care.

The new study demonstrates that combination of enzyme, vasodilators and coumadin significantly improves symptoms and survival of patients with GD and severe PH.

Conclusions

The current status of severe PH in type 1 Gaucher disease reflects extra-ordinary achievements of enzyme therapy after its introduction only a decade ago. When ERT was not available, development of severe PH was a terminal event. The era of ERT has ushered in a new phase in understanding this phenomenon and its treatment. It seems highly likely that the new generation of patients who receive the standard of care treatment for type 1 Gaucher disease will not develop this most feared complication, representing yet another milestone in conquering the ravages of this disease.

Future Research

Further research is underway to understand the genetic basis of type 1 Gaucher disease that exhibits severe PH. We are also studying the effects of new vasodilator drugs in the severely affected patients. Please address any inquiries about this and other Gaucher disease-related studies to Luisa Coraluzzi, Research Co-ordinator, National Gaucher Disease Program, Yale School of Medicine, telephone number 203 785 4795 or visit our web site at http://gaucher.yale.edu.