Abstract

Hepatomegaly is frequent in patients with type 1 Gaucher's disease and is associated with infiltration of the liver with pathological macrophages. Most patients suffer no significant clinical consequences, but a few develop portal hypertension which may progress to parenchymal liver failure. We describe four patients with Gaucher's disease who have developed portal hypertension. We have reviewed their clinical histories and all available histological and radiological material. All had severe Gaucher's disease with multi‐organ involvement, and had undergone splenectomy in childhood. Histologically, this advanced liver disease was characterized by a picture of extreme and advanced confluent fibrosis occupying the central region of the liver. This massive fibrosis is associated with characteristic radiological appearances. The liver histology in these cases is highly unusual and virtually unknown in other conditions. Our studies indicate that without specific treatment the liver disease is progressive and rapidly fatal. However, institution of enzyme replacement therapy with imiglucerase may have beneficial effects even when the condition is far advanced.

Introduction

Gaucher's disease (OMIM nos. 230800, 231000 and 230900) is a lysosomal storage disorder caused by deficiency of the enzyme glucocerebrosidase and characterized by the presence of pathological macrophages laden with glucosylceramide, the principal natural substrate of the deficient enzyme. These Gaucher cells infiltrate parenchymal tissues, predominantly the bone marrow, spleen and liver.1–3 Patients with type 1 Gaucher's disease (the non‐neuronopathic and most common form) develop marked splenomegaly and, before the introduction of enzyme replacement therapy, often required splenectomy. The principal manifestations and disabilities encountered in adulthood are caused by bone‐marrow infiltration, with consequential skeletal disease4 including modelling deformities, pathological fracture and avascular necrosis. Extensive infiltration of the bone marrow also causes haematopoietic failure in splenectomized patients and may contribute to cytopenias in those with intact spleens.

Hepatomegaly is frequently observed in type 1 Gaucher's disease. In a series of 53 patients,5 41 had hepatomegaly, which was classified as mild in 27 patients, moderate in nine and massive in five; but only ten of these patients had abnormal serum tests of liver function and only two suffered complications of portal hypertension. In a comprehensive examination of the hepatic disease that occurs in non‐neuronopathic Gaucher's disease, James et al. conducted a systematic survey of the liver abnormalities in a cohort of 21 patients with type 1 Gaucher's disease.6 All but one of these patients had enlarged livers (two mild, ten moderate and eight massive), and liver biopsies showed that all patients had Gaucher cells present in the liver parenchyma. Eleven patients had abnormal serum tests of liver function. None of the patients had cutaneous stigmata of chronic liver disease at presentation, but two patients subsequently suffered from oesophageal varices with haematemesis, and another patient developed jaundice and ascites.

Therefore, for most patients, infiltration of the liver with Gaucher cells has no significant clinical consequences. There have, however, been sporadic case reports of portal hypertension in patients with Gaucher's disease.7–17 These patients appear to fall into two groups: those with intact spleens7–11 in whom the portal hypertension can be alleviated by splenectomy,8–11 and those who have undergone therapeutic splenectomy10,12,14–17 where intrahepatic obstruction to portal blood flow has been associated with massive infiltration of the liver by Gaucher cells, with associated fibrosis and cirrhosis.6,10,12,15,17

We report a series of four adult patients with type 1 Gaucher's disease who developed severe involvement of the liver complicated by portal hypertension. In all cases the portal hypertension developed after splenectomy and was associated with massive hepatomegaly. We describe the radiological and histopathological features of severe Gaucher's liver disease.

Methods

The cases reported here are part of an 8‐year experience of Gaucher's disease with portal hypertension from two tertiary referral centres for liver disease and transplantation, one of which is also a national referral centre for Gaucher's disease. For this report, all case records have been carefully reviewed and summarized. In each case, other contributing causes for liver disease were excluded by careful clinical, radiological and serological analysis. The normal ranges for serum alkaline phosphatase activity (ALP) differed between the two centres: the normal range for the values given is 30–135 U/l, except in cases marked with an asterisk, in which the normal range is 70–350 U/l. The normal ranges for other serum parameters are: aspartate transaminase activity (AST) 5–35 U/l; alanine transaminase activity (ALT) 0–50 U/l; albumin concentration (alb.) 30–51 g/l. All available histological material was examined by a pathologist (DGDW) and all radiological material by a radiologist (DJL).

Results

The clinical and biochemical features of all cases are summarized in Table 1.

Case histories

Patient 1

This woman presented in 1994 at the age of 45 with fulminant hepatic failure. Over the 4 years before her terminal admission she had suffered episodes of variceal bleeding, which were treated by injection sclerotherapy. She had become hypoalbuminaemic with peripheral oedema and ascites. Two weeks before death, she developed jaundice and intractable oliguria associated with fever and hypotension. She was admitted to hospital with sepsis, associated with an infected hip prosthesis, but died within 24 h of admission, before any specific treatment for her Gaucher's disease could be instituted.

Table 1

Clinical and biochemical features, genotypes and severity score indices of cases

Patient Age at Age at first Bone disease Liver function tests at presentation
 
  Genotype SSI* 
 splenectomy variceal       
 (years) haemorrhage  ALP AST Alb.   

 

 
(years)
 

 

 

 

 

 

 
41 Bilateral THR for AVN 312 16 19 NA 22 
37 Bilateral THR for AVN 1923* 118 32 R463C/Rec NciI 21 
14 No 307 140 32 R463C/L444P 17 
23 AVN of both hips 361 134 27 R463C/INS 2+1 18 
   Generalized osteoporosis      
Patient Age at Age at first Bone disease Liver function tests at presentation
 
  Genotype SSI* 
 splenectomy variceal       
 (years) haemorrhage  ALP AST Alb.   

 

 
(years)
 

 

 

 

 

 

 
41 Bilateral THR for AVN 312 16 19 NA 22 
37 Bilateral THR for AVN 1923* 118 32 R463C/Rec NciI 21 
14 No 307 140 32 R463C/L444P 17 
23 AVN of both hips 361 134 27 R463C/INS 2+1 18 
   Generalized osteoporosis      

* Severity score index (SSI) has been calculated as described in Zimran et al. (1992). NA, not available; ALP, alkaline phosphatase; AST, aspartate transaminase; Alb., albumen (all serum). AVN, avascular necrosis; THR, total hip replacement.

Patient 2

This man was referred in 1994, aged 37, after a variceal haemorrhage, which was controlled by endoscopic injection sclerotherapy. Angiography demonstrated a patent portal vein and a wedged hepatic vein pressure of 14 mmHg, confirming an intrahepatic origin for his portal hypertension. Two years later, he developed decompensated liver failure with ascites, oedema and jaundice after a hip replacement, and had a further variceal haemorrhage, again treated by sclerotherapy. At this time limited enzyme replacement therapy (ERT) with alglucerase at an initial weekly dose of 60 U/kg was commenced, later reducing to 2.5 U/kg. Over the next 4 months, he reported an improvement in his general well‐being, although serum liver test abnormalities persisted (ALP 1555* U/l, AST 218 U/l, alb. 23 g/l). Five months after starting enzyme replacement therapy, he developed septic arthritis of the right hip. The prosthesis was removed with the use of antimicrobial prophylaxis with broad‐spectrum antibiotics. However, 9 days after the surgical procedure, he developed a mixed staphylococcal and candidal septicaemia, which proved rapidly fatal.

Patient 3

This male patient was referred in 1991, aged 18 years, for assessment of his Gaucher's disease. Over the past 4 years, he had suffered from recurrent variceal haemorrhage despite repeated courses of injection sclerotherapy. On examination, he was cachectic, with signs of infantilism, and the liver was massively enlarged. Hepatic angiography revealed a wedged hepatic venous pressure of 21 mmHg with an inferior vena cava pressure of 13 mmHg.

Enzyme replacement with alglucerase at a dose of 5 U/kg twice weekly was started. After 4 months of treatment the patient had gained 3 kg in weight, 5 cm in height and had entered puberty. Although his serum liver tests remained unchanged, he suffered no further episodes of variceal bleeding. He continued to make good progress, but 2 years after presentation, he suffered an acute septicaemic illness due to H. influenzae and died with septicaemic shock within 6 h of its onset.

Patient 4

This patient's skeletal disease has been reported elsewhere.18 He was referred in 1991, aged 24, for treatment of bleeding oesophageal varices, which had failed to respond to a prolonged course of endoscopic injection sclerotherapy, and for consideration of enzyme replacement therapy. He had massive hepatomegaly extending 16 cm below the costal margin. Angiographic measurements showed that the hepatic venous wedge pressure was 19 mmHg with a free hepatic vein pressure of 7 mmHg. Enzyme replacement therapy with alglucerase was started at a dose of 5 U/kg twice weekly. His variceal bleeding stopped immediately, but serum tests of liver function were unchanged. The patient remained well for 5 years, at which time he developed increasing shortness of breath on exertion and platypnoea. Central cyanosis was present, together with widespread peripheral spider angiomata and finger clubbing. Serum liver tests had deteriorated (ALP 443 U/l, ALT 178 U/l, alb. 30 g/l). Extensive intrapulmonary arteriovenous shunting with arterial desaturation was demonstrated, and a diagnosis of hepatopulmonary syndrome19,20 was made. Orthotopic liver transplantation was carried out in 1997: the patient made an excellent recovery and, more than 2 years later, remains well. He continues to receive enzyme replacement therapy and serum liver‐related tests are normal. The manifestations of hepatopulmonary syndrome receded rapidly after transplantation and have not recurred.

Radiology

Radiological imaging was available for patients 1, 2, and 4. There is no pre‐mortem imaging on patient 1, but an MR examination was performed on the necropsy liver specimen. This demonstrated an extensive central area which was low‐signal on T1w images and increased‐signal on T2w images (Figure 1, a and b). Patients 2 and 4 had CT and MR examinations when they first presented. For patient 2, CT showed hepatomegaly with caudate enlargement and widespread areas of calcification and low attenuation. There was low T1 signal on MR imaging, which corresponded to the low attenuation areas seen on CT. For patient 4, CT examination showed hepatomegaly with widespread low attenuation and calcification in the posterior right lobe (Figure 2c). MR imaging showed reduced signal on T1w images with increased T2w signal in the regions of radiodense calcification (Figure 2, a and b).

Figure 1.

Radiology and histopathology from patient 1. MR images of the necropsy liver specimen from patient 1 are shown in a and b. A central low‐signal band is seen in the T1w image corresponding to the increased signal in the T2w image. These MR findings correspond to the confluent central fibrosis seen in the sectioned organ (c). This coronal section through the necropsy liver shows a broad central area of hyaline fibrosis with nodularity of the surviving more peripheral parenchyma. Microphotographs at low magnification (d) show the acellular nature of the fibrous tissue. Higher magnification (e) shows persistence of Gaucher cells within sinusoids and at the edge of the fibrous septa.

Figure 1.

Radiology and histopathology from patient 1. MR images of the necropsy liver specimen from patient 1 are shown in a and b. A central low‐signal band is seen in the T1w image corresponding to the increased signal in the T2w image. These MR findings correspond to the confluent central fibrosis seen in the sectioned organ (c). This coronal section through the necropsy liver shows a broad central area of hyaline fibrosis with nodularity of the surviving more peripheral parenchyma. Microphotographs at low magnification (d) show the acellular nature of the fibrous tissue. Higher magnification (e) shows persistence of Gaucher cells within sinusoids and at the edge of the fibrous septa.

Figure 2.

Radiology and histopathology from patient 4. Axial T1w MR images (a) show extensive low‐signal changes involving much of the right lobe. T2w images (b) demonstrate a more focal area of increased signal within the right lobe (arrows). CT (c) shows areas of ill‐defined low attenuation in the right lobe and parenchymal calcification (arrows) corresponding to the abnormal area seen on T2w MR images. Coronal sections through the explanted liver (d) again show a broad central area of hyaline fibrosis and nodularity of the surviving more peripheral parenchyma. Microphotographs at low magnification (e) show the acellular nature of the fibrous tissue (Elastin Ponceau Stain). Higher magnifications (f) show persistence of Gaucher cells at the edge of the fibrous septa but their complete absence from the parenchyma.

Figure 2.

Radiology and histopathology from patient 4. Axial T1w MR images (a) show extensive low‐signal changes involving much of the right lobe. T2w images (b) demonstrate a more focal area of increased signal within the right lobe (arrows). CT (c) shows areas of ill‐defined low attenuation in the right lobe and parenchymal calcification (arrows) corresponding to the abnormal area seen on T2w MR images. Coronal sections through the explanted liver (d) again show a broad central area of hyaline fibrosis and nodularity of the surviving more peripheral parenchyma. Microphotographs at low magnification (e) show the acellular nature of the fibrous tissue (Elastin Ponceau Stain). Higher magnifications (f) show persistence of Gaucher cells at the edge of the fibrous septa but their complete absence from the parenchyma.

Histology

Whole livers were examined for three patients: necropsy specimens from patients 1 and 3, and an explant liver from patient 4. Sections of the necropsy specimen from patient 2 were also available.

Patient 1

The liver was enlarged and coarsely nodular. Macroscopically, sections revealed a large central area of fibrosis, with focal calcification, surrounded by coarsely nodular cirrhotic liver (Figure 1c). Microscopically, the bands of fibrosis showed central acellular hyalinization, with viable Gaucher cells at their margins (Figure 1, d and e). The surviving liver formed geographic islands, many of which incorporated portal tracts, implying that the fibrosis originated primarily in the perivenular region, although the venules themselves were not apparent. Gaucher cells were noted in small clumps, without associated fibrosis, within the parenchymal nodules (Figure 1e).

Patient 2

Sections of the liver taken at necropsy showed advanced fibrosis with broad fibrous bands involving portal tracts where there was focal ductular proliferation surrounding small parenchymal nodules. The central parts of the septa were acellular, whilst numerous viable Gaucher cells were present at the margins. The nodules showed canalicular cholestasis and contained a few sinusoidal Gaucher cells without fibrosis.

Patient 3

The liver was enlarged and nodular. Sections showed extensive fibrosis with broad fibrous bands separating and surrounding small nodules of hepatocytes, many of which incorporated portal tracts. The septa showed central acellular hyaline fibrosis with Gaucher cells embedded in the more peripheral connective tissue. Gaucher cells were rare in the parenchymal nodules; they were not associated with fibrosis.

Patient 4

The explanted liver was enlarged and nodular. Sections showed extensive central fibrosis with peripheral parenchymal nodularity (Figure 2d). Microscopic examination of the broad fibrous septa showed central hyaline acellular fibrosis, with Gaucher cells embedded in the connective tissue at their margins (Figure 2, e and f). The parenchymal nodules frequently incorporated portal tracts, implying that the septa originated in the perivenular regions. No Gaucher cells were observed in the surviving liver parenchyma, although a few were embedded in pre‐existing portal connective tissue.

Discussion

These four cases represent the severe extreme of the spectrum of liver disease observed in patients with Gaucher's disease. Many patients with this disorder have varying degrees of hepatomegaly, and infiltration of the liver with Gaucher cells may occur preferentially after splenectomy. In most patients, this liver infiltration is clinically silent and the serum tests of liver function are generally normal or only trivially disturbed.5,6

The patients described represent a small minority who develop life‐threatening liver disease. They were all severely affected by Gaucher's disease, with multiorgan involvement and high severity score indices (SSIs)5 (Table 1). All three patients who have had their glucocerebrosidase genotypes determined have disabling mutations in the glucocerebrosidase gene which are associated with an adverse clinical outcome21 (Table 1). In this small series, there is a striking association between severe liver disease and the R463C allele. For all these patients, the first clinical consequence of their liver disease was variceal bleeding caused by portal hypertension and, although none of our patients died as a direct result of gastrointestinal bleeding, three of them continued to have regular episodes of variceal haemorrhage despite injection sclerotherapy.

In addition to their portal hypertension, these patients also had severe hepatic parenchymal disease, as evidenced by biochemical liver function tests and three have suffered episodes of decompensated liver failure. It is clear that the prognosis for those with advanced Gaucher's liver disease is extremely limited. Three of our four patients died within 6 years of their first presentation with variceal bleeding, and the other required liver transplantation. Overwhelming sepsis contributed to the deaths of all three patients in this series, and in two cases this was related to infection of orthopaedic prostheses. The combination of splenectomy,22–24 impaired leukocyte chemotaxis associated with Gaucher's disease,25,26 and defective microbial clearance that characterizes severe parenchymal liver disease,27–29 are likely to make these patients particularly susceptible to bacterial infection. Our experience, and that reported sporadically in the literature, reinforces the importance of avoiding all non‐essential surgical interventions in patients with portal hypertension complicating Gaucher's disease.

The common feature on MR examination is the presence of extensive relatively ill‐defined focal low‐signal areas on T1w images, corresponding to areas of increased signal on T2w images (although often less extensive than on T1, with the remaining corresponding areas iso‐signal with normal liver) (Figure 2, a and b). In the post‐mortem specimen, it was possible to confirm that the abnormal area demonstrated on T1w and T2w images corresponded morphologically to the confluent fibrosis found at necropsy (Figure 1). The MR signal changes are relatively non‐specific, but have been previously described in confluent fibrosis associated with cirrhosis from other causes.30 On MR examinations, these areas of confluent fibrosis may be confused with malignant lesions and additional features such as volume loss, peripheral location and wedge shape have been used to characterize the fibrotic lesions. In patients with Gaucher's disease, these morphological features are of limited use, given the frequent distortion and enlargement of the liver as well as the presence of these lesions both centrally and peripherally. The increased signal on T2w images is a variable finding, and not typical of fibrosis in other organs, and in the study of cirrhotic patients was thought to be due to oedema and inflammation within the fibrosis. Similar focal hepatic lesions have been previously described on MR examinations of patients with Gaucher's disease, although the underlying aetiology was not confirmed.31

The CT examinations demonstrate areas of hypoattenuation both before and after intravenous contrast medium enhancement that correspond with the MR examinations (Figure 2c). These features are also non‐specific, and have previously been described in association with confluent fibrosis in cirrhotic patients.32 However in the two patients in whom pre‐contrast‐enhanced images were available, the finding of focal calcification within parts of the lesions suggests that episodes of ischaemia and necrosis may have a part to play in the pathophysiology of this condition (Figure 2c).

It has previously been noted that the liver histology seen in these patients with severe Gaucher's liver disease is characterized by fibrosis,6,10,12,15–17 although in many of the patients studied by James et al. there was only fine pericellular fibrosis. The common factor in our four patients, all of whom had severe liver involvement, is the extreme and advanced confluent fibrosis observed in these livers. This occupied the whole of the central part of the liver (Figures 1c and 2d) and is of a degree that is highly unusual and virtually unknown in other conditions. Neither viable Gaucher cells nor hepatocytes are seen in the central parts of these fibrotic zones, which are acellular and hyaline with variable dystrophic calcification (which can be seen on CT examinations). In most cases, Gaucher cells are especially numerous in a narrow band at the margins of the septa, adjacent to the islands of surviving parenchyma. Although, in the majority, the fibrosis appears to have commenced in acinar zone 3, it seems improbable that outflow obstruction has played a part in the aetiology of their portal hypertension, since no evidence of vascular congestion was observed in any of the livers.

In the series reported by James et al., infiltration of the liver parenchyma by Gaucher cells was a prominent feature in most of the liver biopsies, and was present in all the patients whose disease had progressed to the stage where fibrous septa were present. In the patients described here, Gaucher cells were predominantly found associated with fibrous tissue, and were relatively inconspicuous within the surviving parenchymal islands, where they appeared generally not to be associated with fibrosis. In patient 1, clumps of Gaucher cells were observed in the parenchymal nodules (Figure 1e), but in the livers from patients 2 and 3, these were much more sparse, and they appear to be entirely absent from the parenchyma of the explanted liver from patient 4 (Figure 2f). These findings imply that institution of ERT can lead to a reduction in the numbers of Gaucher cells infiltrating the remaining liver parenchyma. Indeed, after 5 years of enzyme augmentation, the Gaucher cells had been completely cleared from the parenchymal tissues of the liver explanted from patient 4. Interestingly, all of these patients still had Gaucher cells associated with the fibrous septa, and this population of cells seems relatively insensitive to ERT. Since fibrous tissue is not well vascularized, the persistence of this population of pathological macrophages may simply relate to their inaccessibility to the exogenously administered enzyme.

Our patients also showed a clinical response to the institution of ERT. None of the three described here who have received ERT have suffered further episodes of variceal haemorrhage, even though in patients 3 and 4 prolonged courses of sclerotherapy alone had failed to prevent regular episodes of bleeding. Serum liver function tests improved for both these patients after the introduction of ERT, although for patient 4 they deteriorated again as he developed hepatopulmonary syndrome. Hence it seems that, even when hepatic fibrosis is advanced, the institution of ERT can delay disease progression and stop variceal haemorrhage. Although the established fibrosis cannot be reversed, at the very least this can secure the opportunity for other options, such as transplantation, to be considered.

The mechanism of hepatic fibrosis is obscure and may be multifactorial. Gaucher cells infiltrating bone marrow and in spleen in small groups are generally associated with little or no fibrotic reaction, except where infarction has occurred. The distribution of the fibrous tissue found in these livers, and of Gaucher cells within it, suggests that fibrosis only occurs when the cells reach high density. The absence of viable cells at the centres of the broader fibrous bands suggests that the fibrosis may at least in part have followed necrosis, as suggested by Fellows et al.12 The finding of areas of calcification on CT imaging also suggests episodes of infarction and necrosis. In this context, however, it should be noted that James et al. found no evidence of necrosis in their series of 23 liver biopsies from Gaucher's patients, although most of these showed pericellular fibrosis.6 It is possible that the ischaemia and infarction is secondary to the dense fibrosis; this would explain the acellular hyaline necrosis and calcification that we have observed in the centres of the fibrous bands. The initial fibrosis may not relate to ischaemia at all, but rather represent the effects of local release of fibroplastic factors from the Gaucher cells which behave as chronically activated macrophages.33,34

Address correspondence to Professor T.M. Cox, Department of Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ. e‐mail: jbg20@medschl.com.ac.uk

RHL holds a Wellcome Clinical Scientist Fellowship.

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