Clinical Management of Sickle Cell Liver Disease in Children and Young Adults

Abstract

Liver involvement in sickle cell disease (SCD) is often referred as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This manuscript is based on a round table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH.

Introduction

Mortality from sickle cell disease (SCD) has been decreasing in childhood, but has increased for young adults of 20-24 years of age.¹ Mortality from liver-related complications in SCD is about 7% of all SCD deaths.¹ In this review the term sickle cell hepatopathy (SCH) describes any hepatobiliary dysfunction in SCD. SCH has an estimated incidence of 10-40% in patients with SCD.^2,3 To address the clinical need for a structured approach of diagnosing and managing SCH in children and young adults, a multidisciplinary expert workshop was held at King’s College Hospital, London in 2018. The group comprised of specialists from the three UK paediatric liver centres and one centre from France, adult hepatologists, hepatobiliary surgeons and haematologists who are actively involved in the care and research of this condition.

Clinical presentation and diagnosis of SCH

The polymerization of deoxygenated HbS is the origin of all the complications of SCD. This increases the rigidity of the red cell with consequent damage to the vascular endothelium and vaso-occlusion, resulting in a cascade of pathological processes including infarction, haemolysis, inflammation, hypercoagulability and oxidative stress. All these contribute to liver complications seen in SCD (Figure 1 and Table 1).

Figure 1. Pathophysiology of sickle cell hepatopathy.

The polymerization of deoxygenated HbS is the origin of all the complications of SCD. It increases the rigidity of the red cell with consequent damage to the vascular endothelium and vaso-occlusion, resulting in a cascade of pathological processes, including infarction, haemolysis, inflammation, hypercoagulability and oxidative stress. HbS: haemoglobin S

Permission has been obtained from the illustrator Dr Vassiliki Tzomaka to include the above illustration in the figure of this article.

Table 1. Clinical presentation, diagnosis and management of sickle cell hepatopathy.

Sickle Cell Hepatopathy
	Asymptomatic or Symptoms and Signs of biliary obstruction		Abdominal pain and acute hepatomegaly with jaundice		Jaundice +/-Symptoms and signs of Chronic Liver Disease
Raised Total/Conjugated Bilirubin, ALT and γ-GT
High Ferritin	Biliary Abnormalities on Ultrasound		No Biliary Abnormalities on Ultrasound		Chronic Liver Disease workup
Liver MRI +/- Liver Biopsy	MRCP/ERCP for intervention		↓Hb > 20 g/L	Steady Hb +/- ↑INR	Liver biopsy
Iron overload	Cholangiopathy +/- dominant stricture	Biliary sludge, gall-stones +/- biliary obstruction	Acute Hepatic Sequestration	Acute Hepatic Crisis +/- Liver Failure	AILD Wilson disease HBV HCV Drug toxicity
Management
Iron chelators	Ursodeoxycholic acid +/- dilatation or stent of stricture	ERCP Laparoscopic cholecystectomy Laparotomy	Fluid resuscitation Blood transfusion Exchange transfusion (if ↑LFTs, ↑INR or conjugated bilirubin >50 μmol/L)	IV hydration Blood transfusion HDU/PICU Exchange Transfusion Renal replacement therapy Antibiotics	As per individual diagnosis

ALT: alanine aminotransferase, γ-GT: gamma-glutamyl transferase, MRI: magnetic resonance imaging, MRCP: magnetic resonance cholangiopancreatography, ERCP: Endoscopic Retrograde Cholangiopancreaticography, Hb: haemoglobin, AILD: autoimmune liver disease, HBV: hepatitis B virus, HCV: hepatitis C virus

SCH varies from isolated conjugated hyperbilirubinaemia to liver failure. The main clinical presentations of SCH are discussed below.

Biliary complications

The most common liver pathologies associated with SCD are biliary complications ranging from biliary sludge and gallstones to cholangiopathy and biliary cirrhosis. Increased haemolysis is mainly responsible for hyperbilirubinemia and gallstones. Gallstones are diagnosed on screening or during episodes of acute biliary obstruction. Their prevalence, depending on the population studied, varies from very rare to up to 15%.^4–6 Typical signs of acute cholecystitis are uncommon. More common is intermittent, poorly localized pain of unclear aetiology. Stones and debris leaving the gallbladder may be asymptomatic or cause obstruction leading to abdominal pain, exacerbation of jaundice, pale stools and possibly cholangitis or pancreatitis.

Sickling and occlusion of the end arteries supplying the biliary tree and lack of collateral circulation leads to progressive ischaemic injury of the biliary tree⁷ resulting in cholangiopathy (prevalence 0.8%)³ (Figure 2 and Figure 3).

Figure 2. Sickling in end arteries of bile ducts.

The diagram on the left illustrates the sickling in the end arteries perfusing the bile ducts. The picture on the right is an MRCP of a child with sickle cholangiopathy showing intrahepatic cholangiopathy with dilatations and strictures but no dominant stricture. MRCP: magnetic resonance cholangiopancreatography

Figure 3. Biopsy changes in sickle cell hepatopathy.

Liver biopsy from an 11-year-old showing sinusoidal dilatation (long arrow) and porto-portal bridging fibrosis (short arrows). Sickle cells are visible within the sinusoids in this biopsy from a 12-year-old (B, main image). In acute hepatic sequestration, large numbers of sickled cells can be seen within congested sinusoids (B, lower inset). Iron overload can be seen within cells of the reticuloendothelial system (upper inset) and hepatocytes (long arrow). A liver biopsy from a 17-year-old demonstrating features of autoimmune liver disease in the form of a porto-lobular hepatitis with plasma cell rich interface activity (C, main image). The same child demonstrated cholangiopathic features in the form of concentric periductal fibrosis (C, lower inset) and periductal lymphoplasmacytic inflammation around portal areas (C, upper inset). Cholangiopathic features in the form of duct loss attributed to ischaemic damage demonstrated in panel D. Duct destruction was a prominent feature of this biopsy from a 7-year-old with sickle cell disease and autoimmune liver disease. The upper inset demonstrates a destructive cholangitis affecting interlobular calibre bile ducts (D, upper inset, H&E x200 magnification) and the lower inset demonstrates plasma cell rich inflammation surrounding septal calibre bile ducts (D, lower inset).

Unconjugated hyperbilirubinaemia in SCD is common, but conjugated hyperbilirubinaemia should be investigated for acute obstruction secondary to gallstones, inspissated bile or a dominant biliary stricture. The initial investigation for all biliary pathology is US examination of the liver. Biliary pathology on US should prompt a Magnetic Resonance Cholangiopancreatography which may indicate the need for Endoscopic Retrograde Cholangiopancreaticography (ERCP).

Acute hepatic crisis

Acute sickling of the erythrocytes in the hepatic sinusoids, anaemia and sinusoidal obstruction by the engorged Kupffer cells leading to ischaemia is the underlying mechanism^8,9 of an acute hepatic crisis (also known as acute intrahepatic sickling). This is diagnosed by the association of acute hepatomegaly and pain, increased conjugated hyperbilirubinaemia, variably elevated liver enzymes, with or without liver synthetic failure (defined as prolonged INR >1·5 unresponsive to intravenous vitamin K), and without an obvious biliary obstruction or infection. We include what is known as “sickle cell intrahepatic cholestasis” in the severe presentation of acute hepatic crisis. Sometimes the liver failure presents as part of multiorgan failure.⁹

The disease severity is independent of HbS level and can be classified as follows:

• -
  Mild presentation:

  • ○
    bilirubin less than 80 μmol/L, ≤50% conjugated; (or a bilirubin 2× the steady state)
  • ○
    no liver failure (normal INR).
• -
  Moderate presentation:

  • ○
    bilirubin 80-150 μmol/L, ≥50% conjugated, elevated transaminases, without liver failure; (or a bilirubin 3-5× the steady state)
  • ○
    no liver failure
• -
  Severe presentation:

  • ○
    bilirubin over 150 μmol/L, ≥50% conjugated, elevated transaminases, without liver failure; (or a bilirubin more than 5× the steady state)
  • ○
    elevated conjugated bilirubin (more than 50 μmol/L), with liver failure

Acute hepatic sequestration

Sequestration of large numbers of sickled erythrocytes in the hepatic vasculature is the underlying mechanism in acute hepatic sequestration (Figure 3). Sometimes it is precipitated by acute infections or exposure to hepatotoxic drugs^8,10 and in these cases the patients are cholestatic. It is diagnosed with clinical features of rapid liver enlargement and tenderness with an acute drop of more than 20 g/L in haemoglobin that may be life-threatening.^9,11 Liver function may be normal. The proportion of HbS is not predictive of the severity.

Iron overload

Patients with SCD may develop iron overload as a consequence of frequent requirement of blood transfusion (Figure 3). Hepatic iron overload contributes to about 10% of patient deaths.¹²

Autoimmune liver disease (AILD)

Abnormal liver function tests (LFTs) should be investigated comprehensively to exclude other liver conditions, particularly AILD. In a series of 77 children, 17% had AILD (Figure 3) and 8% viral hepatitis.¹³ AILD is diagnosed on positive autoantibodies (ANA, SMA, LKM1) and compatible histopathology. About 50% of these children also have a cholangiopathy (“overlap syndrome”), sometimes with positive ANCA antibodies and/or the presence of colitis (prevalence 0.03-0.05%).^3,13

Infections and other causes of liver disease

Children with SCD are at risk of acquiring viral hepatitis. They are also at increased risk of bacterial and other infections, due to splenic hypofunction and other immune impairments. Drug induced hepatitis is another consideration.

Monitoring of children with SCD for hepatopathy

Routine monitoring for liver disease is advised at least yearly in SCD patients (Table 2 and Table 3). If serum ALT >2× upper limit of normal (ULN) and/or γ-GT 1·5-2× ULN they should be investigated from a liver disease perspective. Abnormal serum AST (which also reflects rate of haemolysis) and to a lesser degree ALT is described in more than half of asymptomatic patients, but not higher than >2 ULN. Alkaline phosphatase is generally not a good marker of hepatobiliary disease in children given its variation with growth¹⁴, whereas γ-GT is more sensitive and specific.¹⁵

Table 2. Overview of investigations of liver dysfunction in SCD.

Overview of Investigations of Liver Dysfunction in SCD
Asymptomatic: Liver function tests at least once a year Liver ultrasound yearly after the age of 5 years Ferritin yearly if transfused, or monthly if chronically transfused If conjugated bilirubin is raised, will need liver ultrasound If ALT +/- γ-GT is raised needs to be repeated in 3 months’ time If ALT +/- γ-GT raised twice, then chronic liver disease work up If ferritin is >1000, will need MRI liver
Signs of biliary obstruction (jaundice, abdominal pain, pale stool, fever): Liver ultrasound and Liver function tests MRCP/ERCP depending on the pathology
Signs of acute hepatomegaly, abdominal pain +/- jaundice Liver ultrasound, Liver function tests, Hb
Jaundice with or without symptoms and signs of chronic liver disease Chronic liver disease work up Liver ultrasound (+/- MRCP) Immunoglobulins, ANA, SMA and LMK1 (+/- fecal calprotectin, ANCA) Caeruloplasmin and 24 hour urine copper (ophthalmology review for KF rings) Hepatitis B, C and E serology Alpha-1 antitrypsin phenotype If acute presentation, hepatitis A and other viruses like EBV Depending on the case endocrine and metabolic tests, cholestasis gene panel, sweat test Liver biopsy (by hepatology centre)
If chronic liver disease work up negative and LFTs remain abnormal Patient needs to remain under regular hepatology follow up

SCD: sickle cell disease; ALT: alanine aminotransferase; γ-GT: gamma-glutamyl transferase; MRI: magnetic resonance imaging; MRCP: magnetic resonance cholangiopancreatography; ERCP: Endoscopic Retrograde cholangio-pancreaticography; ANA: anti-nuclear antibodies; SMA: smooth muscle antibody; LKM1: liver kidney microsomal antibody; ANCA: anti-neutrophil cytoplasm antibody; KF: Kayser-Fleischer; EBV: Epstein-Barr virus; LFTs: liver function tests.

Table 3. Indications for referral to hepatologist.

Indications for referral to hepatologist
(Symptomatic) gallstones
ALT >2xULN (on two occasions)
γ-GT >2x ULN (on two occasions)
Increased conjugated bilirubin > 2x known steady state level
Co-existing or suspecting additional liver disease like Autoimmune liver disease Infectious hepatitis Wilson disease, NAFLD, others
Liver failure (INR >1·5 unresponsive to intravenous vitamin K with abnormal LFTs)

ALT: alanine aminotransferase, ULN: upper limit of normal, γ-GT: gamma-glutamyl transferase, NAFLD: non-alcoholic fatty liver disease, INR: international normalized ratio, LFTs: liver function tests

Abdominal US should be performed yearly after 5 years of age^5,6. Serum ferritin should be monitored annually in children with a history of transfusion and monthly in case of chronic transfusion. Liver MRI is recommended annually for evaluating iron burden in patients receiving more than 10 transfusions per year¹⁶ or with a ferritin >1000μg/L.

Liver biopsy in patients with SCD is indicated for the investigation of persistently abnormal LFTs in order to rule out coexisting pathology.¹³ It should only be performed when the patient is stable to avoid serious complications.¹⁷ Patients need admission the night before for preparation and discussion with haematology about performing an exchange transfusion.

Management of sickle cell hepatopathy

Management of biliary complications

Most biliary complications are managed conservatively at the acute presentation with intravenous fluids, analgesia and appropriate antibiotics. Choledocholithiasis is the presenting feature in <10% of children with SCD. The ideal therapeutic option is an initial ERCP +/- sphincterotomy, followed by elective laparoscopic cholecystectomy +/- on-table cholangiogram.^19,20 Laparoscopic cholecystectomy for asymptomatic gallstones is controversial. In some countries, cholecystectomy is performed on detection whilst in others the decision is deferred until the young patient can consent.

Cholangiopathy can be helped by ursodeoxycholic acid. It may require dilatation or stenting of dominant strictures by ERCP. Cholangiopathy may progress to biliary cirrhosis and end stage liver disease (ESLD) requiring liver transplant(LT).³

Management of acute hepatic crisis

Usually with acute hepatic crisis, haemoglobin is stable and there is no sequestration. The levels of HbS are not predictive of the severity. Treatment should not be delayed regardless of HbS levels. In mild cases, adequate hydration, usually intravenously is enough. Moderate cases require a simple blood transfusion and daily monitoring of the LFTs until they normalize. Severe cases require:

• -care in a high dependency/intensive care unit.
• -an urgent exchange transfusion: this can be repeated if there is relapse of liver failure after initial improvement regardless of HbS level.
• -twice daily monitoring of LFTs until normalization.
• -renal replacement therapy as required.
• -broad spectrum antibiotics.

Management of acute hepatic sequestration

The patient may present with symptoms of hypovolaemia and will require emergency support with intravenous fluids. A top-up transfusion will be required to increase the haemoglobin to its steady-state level. If there is liver dysfunction with prolonged INR, or a conjugated bilirubin higher than 50 μmol/L an exchange transfusion is required regardless of HbS%.^3,9

Pharmacotherapy for SCH

No medications are proven to improve cholestasis in SCH. Ursodeoxycholic acid does not dissolve pigment gallstones of SCD, but may help in cholangiopathy. Hydroxyurea (hydroxycarbamide) is the only drug approved for the treatment of SCD in Europe²¹ and in the USA it is recommended for all children. Hydroxyurea induces HbF synthesis, which directly reduces the rate of HbS polymerization²² and therefore reduces the frequency of complications related to it.^23,24 Hydroxyurea is metabolized by the liver, but there is no evidence that it causes hepatic damage. No trials explicitly assess its efficacy or safety in SCH, but several studies have shown incidental protection against liver disease, with patients on hydroxyurea less likely to die from liver failure.^24–26

Management of iron overload

Deferasirox (DFX) and desferrioxamine (DFO) are licensed iron chelators in SCD.²⁷ DFO is usually given as a subcutaneous or intravenous infusion in heavily iron-loaded patients. DFX is an orally active iron chelator. LFTs should be checked prior to the initiation of treatment, every two weeks during the first month and monthly thereafter. DFX may contribute to hepatic dysfunction, but the most common cause of liver dysfunction in these patients is the iron itself. For persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, DFX should be interrupted. Once the levels have normalised, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered. DFX is not recommended in patients with severe hepatic impairment.

Management of other causes of liver disease

Management of the other causes of liver diseases is as in patients without SCD. For AILD remission is achievable with prednisolone with or without azathioprine or mycophenolate mofetil.¹³ Ursodeoxycholic acid is added in cholangiopathy.

Haemopoietic stem cell transplantation

HSCT from human leucocyte antigen (HLA) identical siblings can be curative therapy in children with SCD with greater than 95% 5-year overall survival rates.²⁸ Lack of HLA-identical siblings who are clinically unaffected poses a significant barrier in the uptake of this mode of therapy. This led to the development of HSCT programmes using alternative donor sources such as matched unrelated²⁹ or haploidentical donors. Outcomes with these programmes have a higher incidence of serious complications and are reserved only for severely affected children.

In children with AILD or cholangiopathy, HSCT should be discussed early, before the development of advanced liver disease precludes the conditioning necessary for HSCT. HSCT should stop the progression of liver disease. Other potentially curative techniques currently under development are gene therapy³⁰ and gene editing.

Liver transplant

Patients with SCD coming to LT either have co-existent liver disease unrelated to the SCD or have SCH. SCH is a rare and not standard indication for LT. Predicting which patients with SCH will progress to ESLD, understanding whether there are interventions which may stabilise the liver disease and identifying the appropriate time to assess them for LT can be difficult.

The published literature of LT in SCH is limited: 19 cases have been reported in total; 13 adults and 6 children.^3,31–34 In the early experiences, significant morbidity and mortality (one year post transplant mortality over 50%)^31,35 was related to non-liver, but sickle-related end organ damage. Mortality has been substantial in those transplanted in the context of an acute hepatic crisis. These results have been improved upon with better patient selection i.e. transplanting patients with ESLD who are relatively well and stable and with improved haematologic management in the peri-transplant period.

Of the 4 children who underwent LT^3,33 more recently, all survived for more than 4 years. One died 6 years following transplantation from a subdural haematoma. No episodes of graft vascular thrombosis occurred. The fourth child reported³ in spite of aggressive exchange transfusions suffered sickle crises, seizures and rejection. The course of SCD does not appear to be modified by LT, and SCH may recur in the graft.

LT is potential treatment for ESLD secondary to SCH, particularly severe progressive cholangiopathy. However isolated liver transplant still leaves the risk of recurrence of cholangiopathy hence sequential HSCT appears to be an attractive option once the patient has recovered from liver transplant surgery. Sequential liver transplant and HSCT has been successfully performed for primary immune deficiency related liver disease.³⁶

Epilogue

With new and evolving treatments for SCD, the prevalence of SCH is likely to decrease. In the meantime, management of SCH lacks evidence base. Clinical trials looking into the usefulness of early cholecystectomy and into the role of hydroxyurea in the prevention of hepatopathy as an endpoint are required. LT should be considered for very selected patients and in centres expert at managing LT and SCD. HSCT with an available suitable donor would be curative for SCD and avoid the risk of recurrence of SCH in the donor liver. This could be an option while evolving therapies become reality.

Search strategy and selection criteria

References for this review were identified through searches of PubMed with the search terms “sickle cell hepatopathy”, “acute hepatic crisis”, “acute hepatic sequestration”, “sickle cell liver disease” and “children”, without a time constraint. References were also identified from authors’ own files. Only papers written in English and in French were reviewed. The final reference list was generated based on originality and relevance to the specific scope of this Review.

What is known about the topic

1. Liver involvement in sickle cell disease may be associated with significant mortality

2. Mortality from sickle cell disease in young adults has been increasing

3. Management of sickle cell hepatopathy requires multidisciplinary and specialist management

What this study adds

1. A structured approach for the diagnosis of sickle cell hepatopathy

2. Guidance in the management of sickle cell hepatopathy

3. Indications for referral of a child with sickle cell disease to a hepatologist