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© 2001 The Journal of Bone and Joint Surgery, Inc.
Gaucher DiseaseNew Approaches to an Ancient Disease
Gaucher disease is an uncommon autosomal genetic disorder characterized by the deposit of large amounts of a lipid, glucosylceramide, in the cells of the spleen, liver, and bone marrow. The disease occurs because of a genetic fault in the production of a specific enzyme, b-glucosidase, which ordinarily destoys the lipid material. Bone disease consists of a failure to remodel (Erlenmeyer-flask deformity), osteopenia, and medullary and subchondral osteonecrosis, all of which cause, in some patients, severe crippling and disability. A major discovery was the capacity to modify the b-glucosidase by mannose substitution, which allowed it to enter the cell and destroy the lipid. This treatment has greatly altered the lives of patients with this disease, and, when sufficient enzyme was given, has greatly restored the patient’s osseous structure. Gaucher disease is an uncommon disorder, but it offers a spectacular model of the approach now being taken to define and treat many genetic disorders, a number of which are orthopaedic in their manifestations. Gaucher disease is a rare genetic disorder that is classified as a lipid lysosomal storage disease. A product of cell-membrane breakdown, glucosylceramide is stored in the lysosomal bodies of the cells of the reticuloendothelial system as a result of a genetic error in glucosylceramide-hydrolase (b-glucosidase) production. The disease is transmitted as an autosomal recessive and most often causes marked splenomegaly, hematological disorders, and bone abnormalities, all of which may lead to serious functional impairment. This Current Concepts Review describes the disorder in some detail, with particular attention to the osseous manifestations. Although the disease is uncommon, many orthopaedists see patients with osteonecrosis or bleeding disorders and should be concerned about the possibility that these findings may be manifestations of Gaucher disease. Of equal importance, however, is an understanding of the extraordinary strides made by scientists and clinicians in the treatment of this disease over the 119 years since Gaucher first described it1. Not only can the disease now be diagnosed with relative ease but patients who in the past were chronically ill because of the visceral manifestations and severely disabled by the osseous disease can now feel and look well and can live almost normal lives. These remarkable achievements are unique in many ways and are an essential part of this review. The lessons learned from this disease will encourage us to critically examine other rare genetic disorders and to apply similar systems that will allow effective treatment in the future.
Gaucher disease was originally described in 1882 by a French dermatologist, Phillippe Charles Ernest Gaucher, who reported the case of a patient who had massive hepatosplenomegaly and findings suggestive of leukemia but did not become ill or die1. Gaucher believed the disease to be a "benign" leukemic disorder. In 1924, Epstein described the presence of a lipid, cerebroside, in the cells of patients with this disease and declared it to be a lipid storage disorder2. The bone lesions, which in many patients are quite striking, were first defined at almost the same time, and necrotic segments and osteopenia were included in the description3-5. Groen, in 1948, was the first, as far as we know, to describe the genetic transmission of the disorder, and he suggested that it was an autosomal recessive disease6. In a landmark discovery in 1965, Brady et al. defined the enzyme deficiency as a failure of synthesis of glucosylceramide hydrolase (b-glucosidase), which results in the accumulation of glucosylceramide (Fig. 1) in the lysosomal bodies of the cells of the reticuloendothelial system7.
Perhaps the greatest accomplishment in the history of this disorder was the result of work by the same team at the National Institutes of Health. They initially tried to treat patients who had Gaucher disease with the b-glucosidase enzyme, which represented the genetic deficiency, but they discovered that it was not effective because of the inability of the material to cross the cell barrier8-10. In 1991, Barton et al. reported on the use of macrophage-targeted b-glucosidase, which was able to cross the cell membrane and, once inside the cell, to destroy the accumulated glucocerebroside in the lysosomal body11. This therapy made it possible to treat patients with the disease effectively and, indeed, to restore them to reasonably good health with use of regular intravenous administration of the mannose-altered b-glucosidase12-18. More recently, several investigators, including Ginns and Barranger, have defined the genetic error in these patients19. On the basis of these studies, attempts to eliminate the symptoms of the disease by somatic gene therapy are now in progress at several centers16,20-23.
Every twenty to thirty days, red and white blood cells are destroyed and the chemical elements in the cell membrane are liberated (Fig. 2). Most of the elements are either excreted or reutilized. One of these materials is a complex glycosylated cerebroside lipid known as ceramide trihexoside7,24-27. It consists of a sphingosine and a fatty acid (known as a ceramide) to which is attached, in linear sequence, a glucose and two galactoses. In order for this material to be reutilized or excreted, the three sugars must be chemically removed. This is done first with a galactosidase and then with a second galactosidase, which leaves a material consisting of ceramide and glucose (glucosylceramide). If the patient cannot synthesize sufficient glucosylceramide hydrolase (otherwise known as b-glucosidase), the glucosylceramide is imbibed by cells of the reticuloendothelial system (spleen, liver, and bone marrow) and stored in the lysosomal bodies as quite distinct microtubular structures26,28. Because these tubules interfere with programmed cell destruction, they confer on the cell a relative degree of immortality so that the spleen and liver slowly enlarge and the normal bone-marrow elements are replaced by the immortal and characteristic Gaucher cells (Fig. 3) 4,28,29.
Clinically, three forms of Gaucher disease are recognized and are designated as types 1, 2, and 33,7,25,28. Type 1 is the mild-to-moderately severe, slowly progressive non-neuronopathic form seen most commonly in the United States, Europe, and particularly Israel3,25,30. This disorder is found most frequently in the Ashkenazi Jewish population but may arise by spontaneous mutations and can be encountered in any population group3,21,24,31-33. As noted in Table I, the findings are principally visceral, hematological, and osseous, and the patients often have a long life because of the lowering of the cholesterol level (the lipids are utilized in a different system). Type 2 is the infantile form, which is fulminant and severe with prominent neurological findings. Although the patients have visceral and osseous disease, the neurological problems are dominant and devastating and cause death usually by the age of two years24,28,34. There is no ethnic predilection, and fortunately the disorder is rare. Type 3 is much less common than type 1 and occurs most frequently in Swedish persons from Norrbotten. In addition to the osseous, visceromegalic, and hematological problems, these patients also have neurological problems but they are far less severe than those seen in type 23,24,34. The recent findings of the genetic errors in these patients are of some importance (Table II). Five have been described for type 13,30,35. Most of the patients seen in the United States have an abnormality of the N370S allele, which generally is associated with a milder disease course than are the other abnormal alleles.
In untreated patients with Gaucher disease, a number of findings are related to the increasing number of immortalized lipid-containing cells of the reticuloendothelial system. It should be noted, however, that for unknown reasons some patients with the same pattern of enzyme failure have very mild disease whereas others have moderate or severe manifestations and symptoms. In many cases, these individuals are in the same family and have the identical genetic error. The explanation for this is unknown but may be important in learning better ways to control the disease28,33. Although many symptoms and signs of Gaucher disease have been reported, special emphasis should be placed on a few that are quite striking and clearly related to the pathophysiology of the disorder: splenomegaly, hepatomegaly, and hematological, pulmonary, and osseous abnormalities. The spleen in patients with Gaucher disease may be enormous36,37 (Figs. 4-A and 4-B). Splenic infarcts are common and can be painful and at times life-threatening21,24,26,36. Hypersplenism is common, with a resultant pancytopenia and especially thrombocytopenia, leading at times to severe bleeding21,24,38,39. A hematocrit of 25% is common in untreated patients with Gaucher disease, and many patients with severe disease have a platelet count of <70,000/L (<70 ¥ 109/L) 38,40. It should be noted that these values are often corrected quickly after splenectomy but later recur as a result of progressive depletion of the normal marrow elements38,39. Hepatic disease is a late consequence of Gaucher disease. Early in the course hepatomegaly is uncommon, but after splenectomy the liver becomes more enlarged and may become fibrosed and cirrhotic. This may lead to serious errors in metabolism, further reduction in clotting factors, and, sometimes, death21,24,33,41,42. Pulmonary complications are uncommon and limited in extent. They appear to occur with greater frequency in patients with substantial liver disease43-47. Although it is rare, secondary amyloidosis may be a very serious problem48.
Laboratory studies performed for patients with Gaucher disease who have not had a recent splenectomy or treatment with enzyme usually reveal anemia, leukopenia, and thrombocytopenia21,24,37,38. In addition, patients often have an increased acid-phosphatase concentration in the serum (presumably related to the lysosomal location of the glucosylceramide)49. Of some interest is the presence of increased angiotensin-converting enzyme of unknown cause50. Study of the glucosylceramide-hydrolase concentrations in the white cells of the blood shows a deficit, with levels often as low as one-tenth of the normal level26,37. An unusual finding in these patients is an abnormally high level of plasma chitotriosidase, which is presumably related to the abnormal macrophage activation and is believed to be a reflection of the severity of the disease51. As indicated above, the cholesterol level is often quite low because of the decrease in the amount of free fatty acid available for production of this material. Examination of the bone marrow is likely to show abnormal cellular elements and Gaucher cells (often seen best on Wright stain)29. It should be noted that patients with Gaucher disease may have benign hypergammaglobulinemia sometimes associated with an elevated erythrocyte sedimentation rate52,53. This finding may be somewhat confusing and of concern to the physician, since the neoplastic process that occurs with the greatest frequency in patients with Gaucher disease is myeloma54-56. A matter of great concern in terms of surgical procedures is that some patients with Gaucher disease may have a macrophage incompetence for gram-positive bacteria57-59. The cause is unknown but is presumed to be a diminution in the ability of monocytes to destroy bacteria with their lysosomal enzymes57,58. The risk of infection after surgery (prior to enzyme treatment) is often considerably greater than that for other patients. Patients with Gaucher disease seem to have an increased susceptibility to infection with some viruses, particularly the Epstein-Barr virus. Also, symptoms and findings resulting from this infection may persist much longer than those in other patients60.
The splenic, hematological, and hepatic manifestations of the disease are disabling and, in some cases, life-threatening, but the bone and joint manifestations often cause considerable distress to patients with mild disease and even to those who are being treated effectively with the enzyme. It should be noted, however, that the bone disease may worsen after splenectomy, presumably because the reservoir for the Gaucher cells is transferred from the enlarging spleen to the bone marrow. In addition, pancytopenia similar to that seen in patients with hypersplenism may develop, but, in the case of Gaucher disease, it is related to the replacement of the normal bone-marrow population61. The pathogenesis of the osseous problems described below is, in some cases, rather obscure. In addition, there are a number of factors that currently are poorly defined and not well understood. These include (1) an impairment and decrease in the number of osteoprogenitor cells, leading to a severely diminished rate of osteosynthesis, which results in a sometimes profound osteopenia with associated lytic lesions and an increased risk of fractures; (2) marked suppression of osteoclast activity, which leads to remodeling problems for young bones (the Erlenmeyer-flask deformity) and poor fracture-healing at all ages; (3) vascular compromise of unknown cause, resulting in osteonecrosis of the medullary cavity especially affecting the bones of the hip, knee, and shoulder (such problems may also occur as an acute fulminant illness, which is termed the Gaucher crisis); and (4) more frequent observation of osteomyelitis, septic arthritis, and operative wound infections because of a macrophage incompetence for gram-positive infection. The frequency of osteonecrosis in these infected osseous segments makes perfusion with systemic antibiotics much less effective and renders the disease virtually untreatable in many cases. It is evident that the presence of Gaucher cells in the marrow is a major cause of most of the problems listed above, but the exact mechanism by which the bone and bone cells are affected by their presence is not clearly understood.
Table III
Failure to Remodel The most prevalent abnormality in patients with Gaucher disease is a failure of the distal part of the femur and the proximal part of the tibia to remodel, resulting in the classic Erlenmeyer-flask appearance (Fig. 5)21,28,62,63. This finding is noted in approximately 80% of patients and is not a cause of symptoms28. Although rare in other disorders, it is not pathognomonic for Gaucher disease and may be seen in some genetic metaphyseal and diaphyseal dysplasias.
Osteopenia Decreases in medullary bone density and thinning of the cortices are evident in almost all patients with Gaucher disease (Fig. 6)21,28,62. Cortical thinning due to medullary expansion and moderately discrete lytic lesions are not uncommon. Bone-densitometry measurements show a sharp reduction in density compared with that of age-matched controls17,64-66, and measurements of cortical thickness often show striking abnormalities64,67. Fractures are common and sometimes difficult to treat, partly because of the quality of the bone but also because of the bleeding tendency and the risk of infection (Fig. 7)5,28,68.
Osteonecrosis Death of bone because of vascular compromise occurs in many patients with type-1 Gaucher disease and presents in two forms. The first of these, medullary osteonecrosis, is sometimes asymptomatic5,28,62,69. Necrosis of medullary bone causes the death not only of the osseous elements but also of the marrow cells, which include a large number of Gaucher cells. Damage to these cells releases the free fatty acid associated with the sphingosine in the ceramide molecule. The major available counter-ion for the released acid is calcium, which produces a calcium soap, a material that is insoluble in body fluids69. No enzymes are available to destroy this material so a medullary area of markedly increased density, which, despite its appearance, does not seem to strengthen the bone, may be seen for years (Fig. 8)28,69.
The second form of osteonecrosis, corticocancellous disease, principally affects the femoral heads, distal parts of the femora, proximal parts of the tibiae, or proximal parts of the humeri (Fig. 9-A)5,28,29,69-72. These subchondral lesions often lead to pathological fracture and collapse of the osseous end plate, which may result in disabling joint disease. The disorder affects both adults and children. In children, the disorder closely resembles Legg-Calvé-Perthes disease (Fig. 9-B). Regardless of the age of the patient, the disease is often progressive, and some patients may have such severe pain and disability that they become wheelchair-bound at a young age28,70,71. Osteonecrosis is more common in patients who have had a splenectomy73.
Osteonecrosis of either type may produce an acute and quite fulminant pattern of pain and illness known as a Gaucher crisis5,28,62,74. Patients complain of severe pain at the site, they are unable to move the affected part, and they have a high fever, leukocytosis, and an elevated erythrocyte sedimentation rate. Such findings are suggestive of acute osteomyelitis, and the differential diagnosis is difficult5,75,76. The current approach to this problem is to perform a technetium-99m bone scan within two to three days following the onset of the crisis75-78. If the scan shows positive findings over the site, the cause is much more likely to be osteomyelitis. If it shows negative findings over the site, the presence of the bone crisis is suggested. Aspiration biopsies and cultures are also helpful, but, if possible, it is wise to avoid open biopsy or irrigation. Wounds do not heal well, and bleeding may be a serious problem. Although there is no known way to decrease the speed and extent to which the crisis affects the bone, oxygenation appears to be helpful and hyperbaric oxygen therapy seems to have been of value in a few cases described anecdotally.
Unusual Manifestations The second unusual feature is the collapse of midthoracic or cephalad lumbar vertebrae (Fig. 10)5,28,62. The vertebral damage may sometimes occur in multiple segments, leading to curvature or kyphosis, sometimes with spinal cord compression. Patients with this problem, particularly children, may show considerable truncal shortening80.
Another unusual feature of Gaucher disease is the appearance of the long bones on magnetic resonance imaging28,81-84. Because the medullary cavities are filled with Gaucher cells instead of marrow or fat, the long bones have a so-called salt-and-pepper pattern on T1-weighted magnetic resonance images (Fig. 11). The cause of this change is not clear, but it may be related to the shortening of the T1 relaxation time of the Gaucher cells compared with that of the cells of the normal marrow. The change does not seem to occur in epiphyseal sites and often improves with enzyme treatment28,82,84.
Finally, one of the most bizarre osseous abnormalities in these patients is the presence of a gaucheroma. These abnormal collections of Gaucher cells and blood result in a markedly expansile lesion of the bone and often appear as a massive destructive lesion that resembles a giant-cell tumor or an aneurysmal bone cyst (Figs. 12-A and 12-B)85,86.
Patients with Gaucher disease should be carefully examined to define the extent and character of the disease and hopefully to predict future problems, but more importantly to define the need for treatment. The protocol should include genetic studies to prove the existence of the disease, general studies, and studies of the bones.
Proof of the Existence of the Disease
General Studies
Studies of the Bones
Until approximately twenty years ago, the treatment of Gaucher disease was almost entirely supportive. Patients with a low hemoglobin level were given iron or at times blood transfusions, and patients with leukopenia were advised to avoid exposure to circumstances involving a high risk of infection and to take antibiotics when they felt ill. Patients were hospitalized when they had bone crises, splenic infarcts, or serious bleeding episodes and were given supportive care3,21,26. Splenectomy was virtually mandatory in patients with a massive infarct or severe pancytopenia or those in whom the spleen was so large as to be deforming or disabling3,16,24,31. The consequence of such surgery was an increased number of cells in the bone marrow with a resultant increase in bone disease and, more specifically, osteonecrosis61. Bone-marrow transplant was associated with high rates of complications and death, which were related to the ease with which patients with Gaucher disease are infected with bacteria, and approaches such as plasmapheresis were thought to have no value. Bone disease was treated symptomatically62,63. Fractures were managed with fixation devices, but they were associated with a high complication rate, and patients with osteonecrotic destruction of a joint who were thought to be at high risk for surgical complications were treated conservatively. Joint replacement was performed, but it was associated with serious drawbacks in terms of bleeding, high infection rates, and occasionally death40,70,71,79. Many patients with bilateral hip or knee disease were advised to use a wheelchair rather than to risk surgery. Osteomyelitis and septic arthritis were common and were treated with surgical débridement, immobilization, and antibiotic therapy, but, because of the almost inevitable presence of dead bone, they were very difficult to eradicate and at times amputation was required57,75,76,87.
Enzyme Treatment A second discovery was recorded when Brady, Barton, and their scientific and clinical colleagues experimented with a mannose-substituted b-glucosidase3,11,13,27,30,88,89. This material could enter the cell and destroy not only the glucosylceramide but also, in many cases, the offending cell. This led to a marked reduction in the organ and body burden of the offending lipid. In a number of clinical trials, the material (Ceredase [alglucerase]; Genzyme, Cambridge, Massachusetts), which was most readily obtained by extraction and purification from placentas, was administered intravenously every two weeks at a dose initially set at 60 U/kg of body weight. Patients who received the enzyme felt better almost immediately and reported weight gain, less bone pain, and reduced fatigue. Their physicians noted that the patients had a reduction in acid phosphatase levels and increased concentrations of white blood cells, platelets, and hemoglobin over a twelve to twenty-week period. Splenic and hepatic size, as measured on magnetic resonance images, was reduced during the same period. Bone pain lessened, and crises became less frequent in a matter of six to nine months6,15,28,33,49,64,90-92. With use of recombinant-DNA technology, a similar agent known as Cerezyme (imiglucerase; Genzyme) was developed and is currently in use. Its action is identical to that of Ceredase, but it is much easier to produce and has a more certain composition. Although the condition of the bones improved with time, it was of some concern that the improvement had not occurred at the same rate as it had in other organs. With use of the standard dose of Cerezyme (60 U/kg of body weight) every two weeks, substantial improvement in bone densitometry, cortical thickness, and fat-fraction data were not noted until well after one year of treatment89. Furthermore, recent studies have shown that the improvement cannot be maintained if the dose is reduced after two years of treatment, and currently it seems likely that higher doses may be required if the initial success with regard to the treatment of bone disease is to be maintained15,89. Several current trials of treatment protocols with use of bisphosphonate in association with the enzyme have shown some promise but have not yet been completed93,94. It is speculated that when the marrow is restored sufficiently to allow the presence of osteoclasts (which are markedly decreased in number in patients with untreated Gaucher disease), more osteopenia is produced, especially in postmenopausal women. The use of bisphosphonates seems to reduce this problem and tends to increase the bone density. Recently reported experimental studies utilizing gene transfer to alter the body’s management of glucosylceramide are of considerable interest19,20,23. If the RNA coding for the enzyme can be introduced into the cell’s DNA by reverse transcriptase, it is possible that these cells will produce sufficient b-glucosidase to reduce the body’s burden of the offending lipid16,18,20,22. Initial animal studies have shown promise, and currently the genetic therapy is being tried as an approach to the disease in at least two centers. Thus far, some success has been achieved, but it appears to have been relatively short-lived as the altered cells die and the new cells do not seem to carry out the activity as effectively. However, it is likely that this technology will help to provide a better solution to the problem of Gaucher disease. Several attempts have been made to vary the dose level in terms of either the concentration given at each time-period or a change in the time-period itself14,95,96. Many of these protocols have been effective in maintaining the patients’ sense of well-being, the reduction in splenic size, and the hematological parameters, but evidence that none of these protocols leads to an improvement in the bone findings has now accumulated89.
It should be evident from the foregoing discussion that the operative management of patients prior to the introduction of enzyme therapy was fraught with serious complications5,70,71,79. It is important that a patient who requires surgery be treated with increased amounts of Cerezyme for a reasonable period prior to the operative procedure97. The anesthesiologist should be alerted to the problems associated with poor aeration in terms of precipitating a Gaucher crisis74 as well as the threat of excessive bleeding in association with a diminished platelet count or damage to the hepatic prothrombin-production system38,40,41. The patient should have transfusions of blood and/or fresh platelets as necessary. Patients sometimes wish to store their own blood prior to the surgery, and this is acceptable, as is the preliminary use of materials such as erythropoietin to enhance red blood-cell production. The patients should receive prophylactic antibiotic therapy, preferably directed at gram-positive organisms, prior to and for at least four to seven days following the operation75. Anticoagulants should not be administered unless there is some suggestion that the patient has a risk of deep venous thrombosis. Patients should be watched carefully during the first three months after surgery, especially after hip or knee replacement, to be sure that no complications occur.
A fairly well accepted sequential system for understanding and treating genetic diseases involves six stages (Table IV).
Stage I: Description of the Clinical Syndrome The syndrome was first described in 1882 in the remarkable report by Gaucher1. Subsequent authors have added much more information regarding the biological and biochemical characteristics, but it is safe to say that the clinical definition of Gaucher disease is well understood21,24,28,33 and that the understanding of bone problems is reasonably well established (although there are still some exceptions)17,21,28,62,64,65.
Stage II: Definition of the Pattern of Genetic
Transmission
Stage III: Identification of the Biochemical
Abnormalities
Stage IV: Definition of the Biochemical Error
Stage V: Identification of the Gene Error
Stage VI: Treatment by Genetic Alteration An important aspect of this approach, and indeed the beauty of it, is its methodical stepwise solution of a problem. Investigators can have no greater joy than to solve a problem in such a superb and orderly fashion. They should be, and indeed have been, honored for this. Another aspect of this approach that is even more important is its demonstration of a way of dealing with genetic diseases, in particular, for the readers of The Journal, those that affect the bones and are currently treated by orthopaedists. Table V shows an incomplete list of an array of genetic disorders currently being treated by orthopaedists and pediatricians with techniques that are based on analysis of osseous structure, histological observation, or chemical alterations. To date, although the genetic error has been found for most of these disorders, we have no way of doing for patients with these diseases what has been done for patients with Gaucher disease. However, there is little doubt that similar advances in the understanding and treatment of some of these disorders will occur in the not-too-distant future.
It is important for orthopaedic surgeons to understand the progress that has occurred in relation to Gaucher disease. The treatment of genetic bone diseases by molecular biological techniques has a vast potential to alter the way that we treat our patients, and we must maintain a familiarity with the steps and technology by which advances can occur. That is the goal that we all wish to achieve and the one that we must strive for.
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