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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Hepatic sinusoidal obstruction syndrome is frequently linked to high-dose chemotherapy/total-body irradiation in recipients of haematopoietic stem cell transplantation, long-term use of azathioprine after organ transplantation and other chemotherapeutic agents. The incidence of hepatic sinusoidal obstruction syndrome varies from 0% to 70%, and is decreasing.

Disease risk is higher in patients with malignancies, hepatitis C virus infection, those who present late, when norethisterone is used to prevent menstruation, and when broad-spectrum antibiotics and antifungals are used during and after the conditioning therapy. Hepatic sinusoidal obstruction syndrome presents with tender hepatomegaly, hyperbilirubinaemia and ascites, and diagnosis is mainly clinical (Seattle and Baltimore Criteria). Imaging excludes biliary obstruction and malignancy, but cannot establish accurate diagnosis. Hepatic sinusoidal obstruction syndrome may be prevented by avoiding the highest risk regimens, using non-myeloablative regimens, and reducing total-body irradiation dose.

Treatment is largely symptomatic and supportive, because 70–80% of patients recover spontaneously. Tissue plasminogen activator plus heparin improves outcome in <30% of cases. Defibrotide, a polydeoxyribonucleotide, is showing encouraging results. Transjugular intrahepatic porto-systemic shunt relieves ascites, but does not improve outcome.

Liver transplantation may be an option in the absence of malignancy. Prognosis is variable and depends on disease severity, aetiology and associated conditions. Death is most commonly caused by renal or cardiopulmonary failure.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Hepatic sinusoidal obstruction syndrome (HSOS) is the new name given to hepatic veno-occlusive disease (HVOD), an unusual disorder of the liver that presents classically with tender hepatomegaly, hyperbilirubinaemia and ascites. The use of the name HSOS is more appropriate for two reasons: (i) the disease can develop without venular involvement; (ii) obstruction has been shown in experimental studies to originate in the sinusoids.1 The most frequent cause of HSOS in Western Europe and the US is the use of high-dose chemotherapy in recipients of haematopoietic stem cell transplantation (SCT),2–4 a procedure used to manage solid tumours, haematological diseases and autoimmune disorders. In this setting, HSOS is caused by toxicity from high-dose chemotherapy regimens, with or without total-body irradiation (conditioning therapy), and is responsible for considerable morbidity and mortality.2, 4–6

This review on HSOS aims to (i) present the recent data on pathogenesis and risk factors, with an emphasis on endothelial cell injury, (ii) demonstrate how that information has influenced the current clinical management and (iii) discuss updates and future directions of research for both prophylaxis and treatment.

Aetiology

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Hepatic sinusoidal obstruction syndrome was first described in Jamaican patients who ingested foods contaminated with pyrrolizidine alkaloids, such as inadequately winnowed wheat or herbal teas (bush tea disease).7–15 Hepatic sinusoidal obstruction syndrome has also been reported from India, Egypt, Israel and South Africa where it has been related to contamination of wheat and traditional herbal remedies.13, 16 Hepatic sinusoidal obstruction syndrome has been described after all types of SCT, irrespective of the stem cell source, type of conditioning therapy or underlying disease.3, 4 Long-term use of azathioprine after solid organ (liver or kidney) transplantation has been linked to numerous cases of HSOS.17–24 Other chemotherapeutic agents which are linked to HSOS include dacarbazine, actinomycin D, cytosine arabinoside, tioguanine, terbinafine, urethane and anti-CD33 calicheamicin.25–26 Gemtuzumab ozogamicin (GO), a monoclonal antibody used in the treatment of acute myelogenous leukaemia (AML) has also been linked to the development of HSOS,27–31 Such association has not been reduced with a brief course of i.v. corticiosteroid premedication.32 Hepatic sinusoidal obstruction syndrome has also been reported to develop 15 months after the abdominal radiotherapy in a patient with adenocarcinoma of the endometrium with peritoneal dissemination (radiation hepatitis) without evidence of cancer recurrence.33 More recently, HSOS has been reported in association with Wilm's tumour, 6-tioguanine therapy in a patient with Crohn's disease, and in young children who received platelet transfusion containing ABO-incompatible plasma following after haematopoietic transplantation.34–37Table 1 lists many of the conditions associated with HSOS, although the list is not exhaustive.

Table 1.  Recognized causes of HSOS
  1. HSOS, hepatic sinusoidal obstruction syndrome.

Pyrrozolidine alkaloids
Traditional herbal remedies
Post-bone marrow transplant
Medications such as:
 Actinomycin D
 Cytosine arabinoside
 Tioguanine (also in patients with Crohn's disease)
 Mercaptopurine
 Busulfan
 Dacarbazine
 Cyclophosphamide
 Urethane
 Terbinafine
 Anti-CD33 calicheamicin
 Gemtuzumab ozogamicin (Mylotarg)
 Oral contraceptive pills (possibly)
Contamination of wheat
Total-body or hepatic irradiation (high doses)
Platelet transfusion containing ABO-incompatible plasma
Associated illnesses such as:
 Systemic lupus erythematosis with azathioprine therapy
 Familial immunodeficiency
 Wilm's tumour

Incidence and risk factors

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

The incidence of HSOS following the SCT varies from 0% to 70%. This wide range is attributable to the variations in patient's characteristics, diverse criteria for diagnosis, small sample size, variable distribution of risk factors for HSOS in different series and variations in the conditioning immunosuppressive regimens used in each centre.38–43

In contrast to the newer non-myeloablative conditioning regimens, which do not cause HSOS,44 regimens that use cyclophosphamide plus total-body irradiation >13.2 Gy may cause HSOS in up to 50% of patients.40 However, sharp decline in both the severity and the incidence of HSOS has been observed, and appears to be due to: (i) avoiding the cyclophosphamide-containing regimens; (ii) the decrease in chronic hepatitis C virus (HCV) infection amongst transplantation candidates; (iii) the increased use of non-myeloablative regimens; (iv) performing SCT early in the course of leukaemia; (v) the use of i.v., and not oral, busulfan if adults are conditioned with busulfan and cyclophosphamide.1, 45, 46

Aggressive chemotherapy is usually applied to eradicate cancer. This may explain the higher risk of HSOS in patients with malignancies. Many studies have also suggested that individual variability in the metabolism of cyclophosphamide may influence the risk for toxicity.47 Interestingly, a recent study in patients with SCT showed that the haemochromatosis C282Y allele is a risk factor for HSOS and that carbamyl-phosphate synthetase, a rate-limiting urea cycle enzyme, polymorphisms may counteract its adverse effects.48 Additional risk factors for HSOS include HCV infection,49–51 use of norethisterone to prevent menstruation during marrow suppression52 and use of broad-spectrum antibiotics and antifungal drugs during and after conditioning therapy, which may reflect an underlying severe systemic sepsis.40 A list of the risk factors associated with the development of HSOS is shown in Table 2.

Table 2.  Risk factors associated with the development of HSOS
  1. HSOS, hepatic sinusoidal obstruction syndrome; SCT, stem cell transplantation.

1. Pre-existing liver disease (hepatitis C, hepatic fibrosis, cirrhosis)
2. Previous exposure to a myeloablative regimen
3. Past history of HSOS
4. Use of myeloablative regimens
4. High dose of total-body irradiation
5. Use of cyclophosphamide-containing regimens
6. Administration of cyclophosphamide after busulfan
7. Fixed dose of Busulfan's dose (irrespective of plasma concentrations)
8. Use of oral rather than IV busulfan
9. Performing SCT late in the course of leukaemia
10. Carriers of haemochromatosis C282Y allele

Pathogenesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Unlike the most hepatic disorders, HSOS usually presents as portal hypertension followed by the parenchymal dysfunction. This indicates the primary vascular nature of the disease. Pathologically, occlusion of the central venules by subendothelial oedema, haemorrhage or fibrosis can easily be detected, hence the original name, HVOD. However, venular occlusion is not an essential feature of HSOS, although it is more common in severe disease.53 Indeed, sinusoidal involvement is confirmed by both experimental studies and clinical observations, hence the new name, HSOS.

Because sinusoidal obstruction occurs at the onset of the disease, understanding of its underlying mechanisms is a potential key target for therapeutic intervention. This has been examined in various in vitro and in vivo studies and described in detail by Deleve et al.1In vitro cellular studies have demonstrated that toxins and drugs that cause HSOS are more toxic to hepatic sinusoidal endothelial cells (SECs) than to hepatocytes.54–56 This was supported by a study in the rat model of pyrrolizidine alkaloid (monocrotaline)-induced HSOS,57 which showed that the earliest morphological change in HSOS is SECs rounding up, followed by the formation of gaps within the sinusoidal barrier, with subsequent entrance of red blood cells into the space of Disse. While penetrating the space of Disse, blood dissects the sinusoidal lining, and the detached cells from this lining embolize downstream.58 This study confirms that the sinusoids are the primary location of circulatory disruption.58

Many factors are involved in the pathogenesis of HSOS (Figure 1). These include SEC glutathione depletion, nitric oxide depletion, increased matrix metalloproteinases, increased vascular endothelial growth factor (VEGF) and possibly the clotting factors.

image

Figure 1. Factors contributing to the pathogenesis of HSOS. HSOS, hepatic sinusoidal obstruction syndrome; NO, nitric oxide; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.

Download figure to PowerPoint

Glutathione depletion

The role of glutathione depletion in the pathogenesis of HSOS is evidenced by in vitro and the monocrotaline model studies. These include: (i) marked depletion of glutathione in SECs, which precedes cell death, is the commonest biochemical change that is induced by drugs and toxins implicated in HSOS; (ii) maintenance of glutathione in the presence of such toxins prevents cell death; (iii) continuous infusion of glutathione or N-acetylcysteine prevents the development of HSOS in the monocrotaline model;59 (iv) infusion of glutathione 24 h after monocrotaline only reduces the degree of hepatic sinusoidal injury, but to a lesser extent than prophylactic treatment with glutathione. Moreover, Srivastava et al. concluded that the glutathione S-transferase M1 (GSTM1) null genotype predisposes to HSOS and the SECs and hepatocyte damage may be mediated by metabolites of busulfan through the depletion of cellular GSH pool.60

Nitric oxide depletion

In parallel with the decline in hepatic flow, nitric oxide levels in the hepatic vein were shown to decrease.61 Indeed, inhibition of nitric oxide synthesis in the rat model of HSOS caused by sub-toxic doses of monocrotaline aggravated the disease. In addition, infusion of a liver-specific nitric oxide precursor prevents the morphological changes of HSOS and the clinical features. This change suggests an involvement of vasoconstriction and nitric oxide depletion in the development of HSOS.62

Role of clotting factors

The role of clotting disorders in the pathogenesis of HSOS is debatable. Electron microscopic study of liver samples obtained from individuals with bush tea disease revealed no evidence of clotting abnormalities.63 In addition, immunohistochemical studies of autopsy livers did not detect platelets, although fibrinogen and factor VIII were detected in the hepatic veins.64 However, HSOS is a risk factor for the development of transplantation-associated thrombotic microangiopathy (TA-TMA), a disease associated with significantly reduced survival following the allogeneic SCT.65 Also, there is no evidence of clotting abnormalities in the experimental model of HSOS.57

Increased matrix metalloproteins

In the monocrotaline-induced rat model of sinusoidal obstruction syndrome, there was an early increase of matrix metalloproteinase-9 and a later, lower-magnitude increase of matrix metalloproteinase-2 in the liver. In vitro studies of SECs, hepatocytes, stellate cells and Kupffer cells showed that SECs are the major source of both basal and monocrotaline-induced matrix metalloproteinase-9/matrix metalloproteinase-2 activity. Monocrotaline caused depolymerization of F-actin in SECs, and blocking of F-actin depolymerization prevented the increase in matrix metalloproteinase activity. Administration of matrix metalloproteinase inhibitors prevented the signs and histological changes associated with HSOS, and may be a therapeutically viable strategy for prevention.66

Increased vascular endothelial growth factor

The VEGF has various physiological effects including the acceleration of vasopermeability, neovascularization, expression of tissue factors on circulating monocyte/macrophages and coagulability. The role of VEGF in the pathogenesis of HSOS was suggested by Iguchi et al., after their observation of increased serum VEGF that is synchronized fairly well with the development of HSOS in six patients with SCT.67 This observation may indicate a novel therapeutic strategy. However, it has not been reproduced and warrants future study in a larger population.

Clinical picture

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Classic HSOS is characterized by weight gain caused by fluid retention and ascites, tender hepatomegaly and hyperbilirubinaemia in the absence of other causes.39, 40 In HSOS associated with cyclophosphamide-containing conditioning regimens, the syndrome presents 10–20 days after the start of treatment,40 but a later onset may occur with other regimens.68, 69 If patients present with signs and symptoms of liver disease after day 30, they are considered by some investigators to have late-onset HSOS. The course of HSOS is protracted, and symptoms persist for a long period if caused by chronic ingestion of teas or foods containing pyrrolizidine alkaloids. However, HSOS secondary to SCT has a more rapidly evolving course. HSOS is classified according to severity into three stages (Table 3): mild (i.e. the disease is clinically obvious, but resolves without treatment); moderate (symptoms require diuretics or pain medication for cure); or severe (the disease requires treatment and does not resolve before death or day 100, or leads to mortality).40

Table 3.  Classification of HSOS according to its severity
MildModerateSevere
  1. HSOS, Hepatic sinusoidal obstruction syndrome.

If no adverse effect from liver diseaseIf adverse effect from liver diseaseIf HSOS not resolved before day 100
If no treatment is needed. If illness is self-limited.If treatment (such as diuretics and analgesics) is required.If patient dies of HSOS.

Diagnosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

I – Clinical

Diagnosis of HSOS is presumptively based on the signs and symptoms, after ruling out other conditions, such as hyper-acute graft-vs.-host disease (GVHD), cholestasis secondary to sepsis, heart failure, drugs and tumour infiltration (Table 4).70, 71 Clinical criteria for the diagnosing HSOS have been published by the investigators from Seattle and Baltimore (Table 5).39, 41 A study by Blostein et al. compared both sets of clinical criteria, and showed that more patients fulfilled Seattle criteria, whereas patients whose diagnosis was determined by the Baltimore criteria had more clinically significant disease.72 It should be noted that the diagnosis of HSOS can be difficult to establish especially when only one clinical criterion is present, the timing of events is unusual, or there are clinical data suggesting another cause for the liver disturbance.

Table 4.  Conditions that may mimic HSOS
  1. HSOS, hepatic sinusoidal obstruction syndrome; GVHD, graft-vs.-host disease.

  2. * ‘Cholangitis lenta’ is an old entity that describes a form of chronic sepsis associated with biliary tract inflammation and hyperbilirubinaemia in the absence of demonstrable extrinsic obstruction.182

1. Acute liver GVHD
2. Fungal infiltration of the liver
3. Viral hepatitis
4. Cholangitis lenta,* e.g. during sepsis
5. Drug-induced liver disease (ciclosporin, trimethoprim-sulfamethoxazole, penicillins, fluconazole and itraconazole, methotrexate)
6. Constrictive pericarditis and right congestive heart failure
7. Persistent tumour infiltration of the liver
8. Pancreatic ascites and chylous ascites
9. Parenteral nutrition
10. Haemolysis
11. Renal failure
Table 5.  Diagnostic criteria for HSOS
  1. HSOS, hepatic sinusoidal obstruction syndrome; SCT, stem cell transplantation.

Seattle criteria41
At least two of the three following criteria, within the first month after stem cell transplantation (SCT):
 1. Jaundice
 2. Hepatomegaly and right upper quadrant pain
 3. Ascites and/or unexplained weight gain
Baltimore criteria39
Elevated total serum bilirubin (≥2 mg/dL) before day 21 after SCT and two of the three following criteria:
 1. Tender hepatomegaly
 2. weight gain >5% from baseline
 3. Ascites
Modified Seattle criteria40
Occurrence of two of the following events within 20 days of SCT:
 1. Hyperbilirubinaemia (total serum bilirubin ≥2 mg/dL)
 2. Hepatomegaly or right upper quadrant pain of liver origin
 3. Unexplained weight gain (>2% of baseline body weight) because of fluid accumulation

II – Laboratory

Laboratory markers are usually required for early diagnosis, to assess severity, to predict disease outcome, to assess response to therapy, or to detect recurrence. Many studies have observed that patients with HSOS have: (i) an increase in serum bilirubin and aspartate aminotransferase (AST), (ii) an increase in levels of von Willebrand factor and thrombomodulin, suggesting an endothelial injury; (iii) an increase of coagulation activation markers, such as protein fragments 1 + 2 and thrombin ± antithrombin complexes; (iv) a decrease in the concentrations of natural anticoagulants, such as protein C and antithrombin III; (v) an increase in procoagulants such as factor VIII and fibrinogen; (vi) a decrease in the activity of von Willebrand factor protease.73–81

High serum bilirubin level is a sensitive index of HSOS, but is non-specific as it may also be indicative of a number of other disorders in the transplant setting. Serum (AST) levels >750 IU/L indicate poor prognosis.82, 83 Also, early cases of HSOS showed elevated serum levels of procollagen III,84, 85 or its N-terminal propeptide (P-III-P)86 even before the appearance of any clinical or laboratory sign, and can be considered as an early marker for HSOS in children. P-III-P values in adults are probably useful in predicting and monitoring the clinical course of HSOS. This was confirmed by Tanikawa et al. in a 44 consecutive adult patients undergoing allogeneic SCT. Moreover, the serum P-III-P level before start of conditioning might indicate patients at risk for developing HSOS.87 In addition, low serum protein C levels can discriminate between patients with and those without HSOS. However, given that the difference between these two groups is already evident before conditioning,88 this test is considered as a predictive rather than a specific marker. Moreover, plasminogen activator inhibitor 1 (PAI-1) was found to be significantly elevated at the time of bilirubin increase in patients with bone marrow transplantation-associated HSOS, when compared with those with GVHD or other causes of liver damage, and permits a correct differential diagnosis of HSOS in patients without sepsis.89–91 Furthermore, Park et al. have shown that the impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of HSOS after SCT.92

III – Imaging

The common ultrasonographic findings reported in patients with HSOS include ascites, hepatomegaly, attenuated hepatic flow, hepatic veins or biliary dilatation. Although none of these findings is sensitive enough,93–98 ultrasound helps in excluding extrahepatic biliary obstruction and malignant infiltration of the liver or the hepatic vasculature. Nicolau et al. observed that a gall-bladder wall thicker than 4 mm is present in patients with HSOS, and that there was a correlation between such thickening and the HVPG.95 This finding is non-specific and can be associated with any case with hypoproteinaemia. Therefore, there is no definite ultrasongraphic feature that is strongly associated with early HSOS, when a definitive diagnosis is most needed.99

Pulsed Doppler ultrasound may be of prognostic value,100 rather than a diagnostic tool. It usually shows a decreased or inverted portal blood flow, which is a relatively late finding in patients with HSOS.96 In addition, Ghersin et al. reported segmental portal flow reversal as an early sign of HSOS in an infant.101 This needs to be confirmed in a bigger study.

Magnetic resonance imaging (MRI) can be used as a complementary technique following the non-conclusive ultrasound examination. In addition to its ability to show hepatomegaly, hepatic vein narrowing, periportal cuffing, gall-bladder wall thickening, marked hyperintensity of the gall-bladder wall on T2-weighted images, ascites and pleural effusion,102 MRI has recently demonstrated patent hepatic veins and patchy signal enhancement compatible with sinusoidal congestion in two patients with HSOS. Therefore, the diagnosis of HSOS should be evoked when patchy liver enhancement suggestive of sinusoidal congestion is observed in the absence of hepatic vein thrombosis and congestive heart failure.103

IV – Haemodynamics

A transvenous, usually jugular, study [measurement of the hepatic venous pressure gradient (HVPG) ± liver biopsy] is only indicated when the patient is deteriorating, when diagnosis is a problem, and when therapeutic measures that may be potentially hazardous are planned. It may also be indicated for research purposes, and should only be performed in the tertiary experienced centres. The transvenous approach is relatively safe in the experienced hands, and is more useful than others as it allows for the detection of the presence or absence of intrahepatic portal hypertension. In addition, it allows transvenous liver biopsies.104–106 The benefits of liver biopsy should always be weighed against the potential risk of bleeding. In patients without previous liver disease, an HVPG higher than 10 mmHg is >90% specific and 60% sensitive for HSOS, and helps differentiating HSOS from GVHD. There is a correlation between HVPG and the severity of HSOS. Patients who survive HSOS usually show lower HVPG than those who die. Many studies have shown that transjugular liver biopsies can be obtained in >90% of the cases with a low incidence of false-negative outcomes, attributable to the patchy nature of this disease.64, 105–107

In addition to the transjugular route, liver biopsies can be obtained via a laparoscopic approach. This technique provides more informative biopsies, and was shown to be safe when applied in a group of 29 patients, including 24 SCT recipients, with hepatic dysfunction after chemotherapy.108

V – Histopathology

The most distinctive histolopathological feature of HSOS is a thickening of the subintimal zone of central and sublobular venules. This produces concentric or eccentric luminal narrowing.19, 82, 109 In early stages of the disease, thrombosis does not occur and inflammatory cells are few or absent, but biopsies show marked widening of the subendothelial zone by the fragmented red cells, oedema and fibrinogen that can be identified by immunochemistry or the Lendrum's MSB technique using Mallory's stain.64 These changes are focal, and can be difficult to distinguish, on routine stains, from acute venous outflow obstruction (sinusoidal dilatation, centrilobular congestion and hepatocyte loss). Connective tissue stains (trichrome techniques) may help in this situation. In the intermediate stages, the subintimal lesions become fibrotic and acquire an ingrowth of small vascular channels. Thus, the affected venules get incorporated into the centrilobular scarring, and can only be identified by connective tissue stains. In later stages, the non-specific change of chronic venous outflow obstruction predominates leading to perivenular fibrosis, pericellular fibrosis, central-central fibrous bridges and eventually cirrhosis. Varying degrees of hepatocyte hyperplasia and peliosis hepatis may accompany HSOS particularly in renal transplant patients treated with azathioprine.19

Prevention

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Given the very high mortality rate in patients with severe HSOS, it is critical to prepare effective preventive strategies during haematopoietic SCT.110 The currently available preventive measures of HSOS are (i) to identify individuals at high risk and (ii) to avoid exposing them to the highest risk regimens (Table 6). The major risk factors are pre-existing liver disease, notably hepatitis C, hepatic fibrosis or cirrhosis, previous exposure to a myeloablative regimen and past history of HSOS. Use of the non-myeloablative regimens, which are not hepatotoxic, represents the only available policy to avoid HSOS in patients with hepatic fibrosis.44 Reduction of the dose of total-body irradiation,111 administration of cyclophosphamide before rather than after busulfan (Bu-Cy regimen)112 and avoidance of cyclophosphamide are all potential strategies to reduce the risk of HSOS. Some investigators have demonstrated that adjusting the dose of busulfan, based on the plasma concentrations, is of benefit, although this was not confirmed in other studies.113–120 The benefit obtained from adjusted busulfan dosing may depend on other factors, such as the age of the patient and the dose of cyclophosphamide. A study by Kashyap et al. has shown that the incidence rate of HSOS is significantly lower and the 100-day survival rate significantly higher in patients treated with IV busulfan than in patients treated with oral busulfan when used as part of a BuCy2 preparative regimen for allogeneic haematopoietic SCT.121

Table 6.  Strategies to prevent HSOS
  1. HSOS, hepatic sinusoidal obstruction syndrome.

Identify subjects at risk:
Patients with liver disease
Patients previously exposed to a myeloablative regimen
Patients with past history of HSOS
Avoid exposing them to risk factors:
Use non-myeloablative non-hepatotoxic regimens
Reduce dose of total-body irradiation
Avoid cyclophosphamide
Adjust the dose of busulfan
Change the route of buslfan
Other measures (of no proven efficacy):
Heparin
Pentoxifylline
Prostaglandin E
Ursodeoxycholic acid

Although low-dose heparin and molecular weight heparin (LMWH) appeared to be safe, three prospective randomized-controlled trials (RCT) failed to show any significant value of low-dose heparin122–124 or LMWH in the prevention of severe HSOS in patients with autologous and allogeneic bone marrow transplantation. Other retrospective and cohort studies demonstrated similar results.125–127 Therefore, larger RCTs are needed to address whether severe HSOS can be prevented in high-risk patients.

Many other preventative strategies have been tried, such as prostaglandin E1, ursodeoxycholic acid128–131 and pentoxifylline.132–136 However, none of these modalities reduced the incidence of fatal HSOS, although ursodeoxycholic acid appears to be promising and well tolerated.

Treatment

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

The advance in the knowledge about the pathophysiology of HSOS has paved the way towards the proposal of therapeutic measures, including supportive care, PGE1, heparin plus r-tPA, defibrotide (DT), transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation, in addition to others (Table 7).

Table 7.  Treatment options of HSOS
ActionComment
  1. HSOS, hepatic sinusoidal obstruction syndrome; NAC, N-acetylcysteine; TIPS, transjugular intrahepatic portosystemic shunt; t-PA, tissue plasminogen activator.

No treatmentIn mild cases as spontaneous recovery occurs in 70–85%
Supportive measuresAs dialysis and ventilation, if needed
Treat ascitesBy salt restriction, diuretics, paracentesis or TIPS
Heparin + t-PAShowed improvement in <30% of cases
Defibrotide (DT)For severe cases. Leads to symptomatic resolution in 35–55% of cases
TIPSDecompress the portal circulation, relieves ascites, but effect on outcome is controversial
Liver transplantationIn the absence of malignancy
Others such as NAC, prednisolone & haemofiltrationOnly tried in few cases

Supportive measures

As 70–85% of patients with HSOS recover spontaneously, the treatment is mainly supportive. Ascites is treated with sodium restriction, diuretics and therapeutic paracentesis for discomfort or shortness of breath. Other supportive measures, such as haemodialysis and mechanical ventilation, were used in patients with HSOS associated with multiorgan failure, without any improvement in the outcome.40, 137–139

Heparin plus tissue plasminogen activator (t-PA)

In patients with severe HSOS, heparin plus t-PA have been tried by many investigators and showed improvement in <30% of patients.140–142 More encouraging results were shown by another two small series.143, 144 It should be noted that this combination should be avoided in patients with increased risk for pulmonary or intracerebral haemorrhage as well as those with pulmonary or renal failure.141

Defibrotide

Defibrotide, a single-stranded polydeoxyribonucleotide that has specific-binding sites on vascular endothelium, may have antithrombotic, anti-ischemic and thrombolytic effects and reduces leucocyte rolling and adherence to endothelium. Therefore, it has been used in the treatment of many vascular diseases, and is a promising treatment of HSOS. The suggested mechanisms of action of DT include: (i) stimulation of endothelial-cell release of t-PA; (ii) up-regulation of the release of nitric oxide, prostacyclin (PG I2), prostaglandin E2, thrombomodulin and t-PA both in vitro and in vivo; (iii) decreased release of plasminogen activator inhibitor-1; and (iv) stimulation of the adenosine receptor.145–152 Moreover, DT has been shown to decrease thrombin generation, tissue factor expression and endothelin activity.153–157

In many uncontrolled trials and a case report of patients with moderate-to-severe HSOS who were treated with DT, 35–55% experienced complete symptomatic resolution without significant side effects, and 26–42% survived >100 days.158–160 The reported high mortality of severe HSOS makes these results very encouraging. However, DT is not widely available in many countries, and the relatively small number of patients in most of these studies has precluded a more detailed analysis of the results of such treatment.161–165

TIPS

Transjugular intrahepatic portosystemic shunt insertion has been used to decompress the portal circulation, and relieve ascites in some patients with HSOS, but in some others this procedure has been shown to worsen the process and did not improve the outcome.166–171

Liver transplantation

Liver transplantation has been reported as a treatment of HSOS.172–174 However, it should be considered only in patients with severe liver failure who are expected to have a good outcome in the absence of liver disease, and those who have undergone bone marrow transplantation for benign disease. Liver transplantation is usually contra-indicated when malignancy is present because of the high rates of recurrence.

Other treatments

Many other therapeutic modalities have been tried in patients with HSOS. These include N-acetylcysteine, methyleprednisolone and charcoal haemofiltration.175–178 However, these modalities were only presented in case reports, and need further testing either as individual therapy or in combination with others in multi-centre RCTs.

Prognosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References

Although patients with severe HSOS have marked hyperbilirubinaemia, death rarely results from liver failure and is most commonly because of cardiopulmonary or renal failure. Published case mortality rates range from 0% to 67%, largely because of differences in diagnostic criteria for HSOS. Mortality rates for regimens that contain cyclophosphamide may be in the range of 30%,38–40, 179, 180 and this may be higher than the mortality rates for patients treated with other alkylating agents. In two large studies, recovery from HSOS that is caused by cyclophosphamide-containing regimens occurred in >70% of patients in 15–25 days after onset.38, 40 A third study of HSOS secondary to other alkylating agents reported recovery in 84% of patients.68 The clinical data that best correlate with patients’ outcomes are the amount of weight gain and the bilirubin concentration. The HVPG also seems to be helpful in predicting patients’ outcomes. Published graphs can be used to predict the outcome of HSOS in patients who are treated with cyclophosphamide-based regimens.181

Key points

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References
  •   (i)
    HSOS can develop without venular involvement, and the obstruction originates in the sinusoids.
  • (ii)
    HSOS presents classically with tender hepatomegaly, jaundice and ascites.
  • (iii)
    High-dose chemotherapy plus total-body irradiation is the commonest cause of HSOS in the Western world.
  • (iv)
    The toxins and drugs that cause HSOS are more toxic to hepatic SECs than hepatocytes.
  • (v)
    Diagnosis of HSOS is mainly clinical, while liver biopsy helps differentiate HSOS from other hepatic parenchymal diseases.
  • (vi)
    The only preventive measure of HSOS is to identify individuals at high risk, and to avoid exposing them to the highest risk regimens.
  • (vii)
    Treatment is mainly supportive, and DT therapy appears to be encouraging.
  • (viii)
    Death rarely results from liver failure and is most commonly because of cardiopulmonary or renal failure.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Aetiology
  5. Incidence and risk factors
  6. Pathogenesis
  7. Clinical picture
  8. Diagnosis
  9. Prevention
  10. Treatment
  11. Prognosis
  12. Key points
  13. References
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