A rare disease in adult women: Gaucher disease

Abstract

Gaucher disease is a rare, autosomal recessive disorder caused by inborn errors of metabolism. Globally, more than 27 million people are born each year, and approximately 19,000 neonates are born with lysosomal storage disease. We report a rare case of Gaucher disease in an adult female patient of non-consanguineous parents in a subtropical area of Jiangxi Province, China. This area has a high prevalence of schistosomiasis. The diagnosis of this case posed a great challenge because of the possible differential diagnoses of pancytopenia with hepatomegaly and giant splenomegaly. The key component of the patient’s diagnosis was her medical history in which it was documented that her brother had died of hepatocellular carcinoma of unknown origin. We diagnosed the patient through a combination of a pathological biopsy and imaging plus the patient’s medical history.

Introduction

Gaucher disease (GD) is the most common sphingolipid disorder. Philippe Gaucher first described a patient with massive splenomegaly without leukaemia in 1882. GD is a rare autosomal recessive disorder of lysosomal storage disorders caused by a deficiency of the lysosomal enzyme glucocerebrosidase, resulting in the accumulation of undegraded glucocerebroside in the lysosomes of macrophages. ¹ In the general population, the incidence of GD varies from 0.4 to 5.8/100,000 inhabitants, with the lowest prevalence in the Asia-Pacific region. ¹ The most common symptoms of GD are anaemia, thrombocytopenia, splenomegaly and/or hepatomegaly, and potentially severe skeletal involvement. The phenotypes of GD are varied, but three clinical forms have been identified. Type 1 is the most common phenotype and usually causes no neurological damage, while types 2 and 3 are characterised by neurological dysfunction. ² Disease-specific treatments for GD include intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Inhibitors of oral glucose ceramide biosynthesis (miglustat or iglustat) may also be used as a treatment for GD. ³

We report a rare case of GD in a female adult. This disease was undiagnosed for approximately 2.5 years from the onset of symptoms to its diagnosis. The awareness of a few clinical findings could have led an earlier diagnosis in this patient.

Case presentation

A woman in her early 40s presented to the outpatient clinic with recurrent malaise, nausea, and bloating for more than 3 years. She was living in a remote mountainous area of Lichuan County, Jiangxi Province, China Her history of symptoms, such as recurrent bloating, jaundice, hypersplenism, splenomegaly, and history of travelling, were taken into consideration, which were not helpful in making a differential diagnosis. When we made further enquiries, she confirmed that her brother had died of a similar disease and suffered from hepatocellular carcinoma with GD as the main causative agent.

On a clinical physical examination, the patient was in a clear state of mind and her basic vital signs were stable. She was pale, and palpation 5 cm below the ribs showed hepatomegaly and that 15 cm below the ribs showed splenomegaly. Taking into account the prevalence of subtropical diseases in China, differential diagnoses of portal hypertension, malignancy, autoimmune disease, myelodysplastic syndrome, and Niemann–Pick disease were made in that order.

In ancillary examinations, a complete blood count showed that the number of blood cells was lower than normal, with a platelet count of 48 × 10⁹/L and white blood cell count of 2.93 × 10⁹/L. Her haemoglobin concentration was 100.00 g/L and her haematocrit was 30.10%. A peripheral blood smear showed pancytopenia with mild heterocytosis. Liver function tests showed that the patient had a high direct bilirubin concentration, and renal function tests showed that she had a low creatinine concentration. Tests for human immunodeficiency virus and hepatitis B and C viruses were negative. Upper gastrointestinal endoscopy was recommended to determine if oesophageal varices was present and to assess the risk of splenectomy. Upper gastrointestinal endoscopy showed non-atrophic gastritis.

GD was confirmed by a pathological examination (Figures 1, 2). Ultrasound images showed findings consistent with a storage disorder. We observed an enlarged right lobe of the liver, spleen thickness of 104 mm between the intercostal spaces and 126 mm below the umbilicus, and heterogeneous echogenicity of the spleen parenchyma (Figure 3). The patient also underwent sequencing of the GBA gene for GD, and this showed a pure missense mutation in the exon coding region of the GBA gene. These features are consistent with GD.

Figure 3.

Ultrasound images of the patient. The right lobe of the liver is enlarged in size, and the left lobe of the liver cannot be seen. The hepatic envelope is smooth. The spleen is approximately 104 mm thick between the ribs and 126 mm thick below the umbilicus, with uneven echogenicity of the splenic parenchyma. There are several slightly high echogenic masses of varying sizes, and several echo-less, liquid, dark areas of varying sizes in the splenic region.

Figure 1.

Histology shows the presence of hepatic lobular structures. Additionally, hepatic sinusoids are characterised by clusters of enlarged Kupffer cells with an abundant cytoplasm, pale colour, and fibrous or circular corrugated shape.

Figure 2.

Histology shows the loss of the splenic corticomedullary stroma. A large number of histiocytes can be seen proliferating in the sinus. The cells have a large cytoplasm and are lightly stained by haematoxylin and eosin, and some of the cells are phagocytosed with ferric haemoglobin.

Glucosinolate treatment could not be started immediately because of the patient’s poor financial situation. We had several discussions with the patient and approached a pharmaceutical company, but she declined treatment. In the meantime, her pancytopenia had worsened and she had considerable abdominal distension and a huge spleen. Therefore, splenectomy was planned, and she indicated that she was aware of the situation and consented to the procedure. She underwent splenectomy + liver tissue biopsy under general anaesthesia. After splenectomy, a repeated complete blood count showed a white blood cell count of 8.23 × 10⁹/L, red blood cell count of 4.11 × 10¹²/L, haemoglobin concentration of 118 g/L, and platelet count of 123 × 10⁹/L. A telephone follow-up showed improvement in the patient’s condition. Consent for all treatments was obtained from the patient. This case report does not contain identifying information about the patient. The reporting of this study conforms to the CARE guidelines. ⁴

Discussion

GD is caused by an inborn error of metabolism due to a mutation in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase. ⁵ Glucocerebrosidase is a lysosomal hydrolase that cleaves glucose ceramide to ceramide and glucose and glucosyl sphingomyelin to sphingomyelin and glucose. ⁶

Generally, there are three clinical subtypes of GD based on neurological clinical signs and the age of onset. The typical clinical manifestations of type 1 are organomegaly, skeletal manifestations, anaemia, and thrombocytopenia. ⁷ GD type 1, which is the chronic, non-neurological adult form, accounts for more than 95% of all cases and is the most common type. GD type 2, which is an acute neurological form with onset in infancy, is the rarest form with devastating and progressive neurodegeneration, often leading to death in infancy or early childhood. ⁸ GD type 3 (chronic neuronopathic), is a subacute neurological form with a slower progression of neurological symptoms and later onset of the disease. ⁹

The diagnosis of GD is often accompanied by delays because its diagnosis requires the use of invasive and resource-intensive procedures, such as pathological biopsies, molecular genetic tests, and enzyme activity assays. ¹⁰ A multidisciplinary combination of internal medicine, paediatrics, radiology, pathology, and molecular biology is beneficial in the treatment of GD. Treatment modalities include ERT, substrate reduction therapy, bone marrow transplantation, and splenectomy. If required, blood transfusions can also mitigate the progression of GD. ¹¹ ERT is effective in altering the size of the liver and spleen, and improving bone abnormalities and blood disorders, but it is currently costly and financially prohibitive in developing countries. ¹² Substrate reduction therapy is used as a second-line treatment for GD, and it reduces complex sphingolipid biosynthesis via the inhibition of glucosylceramide synthase. ¹³ In cases where ERT is not possible, bone marrow transplantation can be offered to patients. Splenectomy is also an option for the treatment of painful splenomegaly, but it tends to lead to encapsulated bacterial infections.

Conclusions

Patients with GD who have undergone splenectomy have normalised blood cell counts and recover well without the need for other treatments. We found that our patient had normal blood counts and other indicators were normal after splenectomy. Patients with GD are often accompanied by a long disease course, diagnostic difficulties, and a variable prognosis, depending on the severity of the organ systems involved and the additional socio-economic interactions of the individual. The findings in this case highlight the need for a multifaceted analysis of the patient’s condition, which will not only help in early diagnosis and treatment, but will also positively affect the patient’s prognosis if they have GD. A lack of awareness of GD among treating physicians, considerable underreporting, a lack of tertiary genetic referral centres, and a severe lack of universal health insurance policies have resulted in low prevalence estimates. Many patients travel long distances to seek treatment, and the various costs of accommodation, travel, repeated hospital visits, and hospitalisation add to the financial burden. In reality, the prevalence rate of GD is likely to be higher than that reported in the published literature, which indicates the urgent need to develop effective and affordable treatment programmes.