REVIEW

Lymphoma and Hematological

Conditions: II. Sickle Cell
Hepatopathy and Other
Hematological Diseases
Oliver Tavabie, M.R.C.P., and Abid R. Suddle, M.D., F.R.C.P.

This review summarizes the liver disease found in sickle cell
hepatopathy and other common hematological conditions.
SICKLE HEPATOPATHY
Sickle hepatopathy is an umbrella term, encompassing
diverse hepatic pathology arising from a variety of insults
to the liver which can occur in patients with sickle cell
anemia.1,2 It occurs predominantly in patients with
homozygous HbSS disease, and to a lesser extent in
patients with HbSC disease or HbSb-thalassemia. Liver
disease can result directly from the effects of sickling
within the liver, from complications related to the multi-
ple blood transfusions some patients require, or be coin-
cidental. The clinical spectrum of liver disease includes
mild abnormalities of liver function in asymptomatic
patients, to dramatic acute clinical crises associated with
an acute liver failure phenotype, to cirrhosis with liver
failure. Table 1 outlines a classification for sickle
hepatopathy.
The incidence of sickle hepatopathy is difficult to
define. Abnormalities in standard liver laboratory tests
are common in sickle cell anemia and do not necessarily
reflect intrinsic liver disease. For example, a moderate
increase in bilirubin (predominantly unconjugated) and
aspartate aminotransferase may be as a consequence of
hemolysis. The acute liver syndromes usually occur in the
clinical context of a vasoactive crisis. The natural history
of sickle hepatopathy is not well understood. A particular
challenge is identifying which group of patients is at risk
for development of progressive chronic liver disease.
Patients with chronic cholestasis often report noting
increased icterus during previous acute crises. Liver
biopsy is associated with a high risk for bleeding,3 espe-
cially in the acute liver syndromes, and should be consid-
ered only if results will materially affect management.
This is not usually the case. The evidence basis for medi-
cal treatments is not strong. There is a need for good-
quality, prospective studies to define natural history and
provide evidence for specific interventions.

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ERCP, endoscopic retrograde cholangiopancreatogra-
phy; HBV, hepatitis B virus; HCV, hepatitis C virus; MRI, magnetic resonance imaging; NRH, nodular regenerative hyperplasia; RUQ,
right upper quadrant.
From the Institute of Liver Studies, King’s College Hospital, London, SE5 9RS United Kingdom.
Potential conflict of interest: Nothing to report.
Received 13 April 2016; accepted 4 May 2016

View this article online at wileyonlinelibrary.com

C 2016 by the American Association for the Study of Liver Diseases
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6 | CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD
REVIEW Sickle Cell Hepatopathy and Other Hematological Diseases Tavabie and Suddle

TABLE 1. CLASSIFICATION OF SICKLE HEPATOPATHY Recommendations regarding management of the spe-

cific clinical syndromes encompassed within sickle hepat-
Chronic
opathy are listed in Table 2. Sickle cell intrahepatic
Acute Liver Disease Liver Disease
cholestasis is a severe acute presentation and is often
Related to Sickling Process
fatal. It is thought to be as a consequence of widespread
Acute sickle hepatic crisis Chronic cholestasis
sickling within the sinusoids, with resultant ischemia and
Hepatic sequestration Biliary-type cirrhosis
hepatocyte injury. Striking jaundice can develop (levels of
Sickle intrahepatic cholestasis
up to 270 lmol/L or 15 mg/dL have been reported) in
Related to multiple blood transfusion
association with renal failure and coagulopathy. Full sup-
Viral hepatitis B and C Chronic viral hepatitis
portive management is instituted, and there is some evi-
Miscellaneous
dence for the use of vigorous exchange transfusion.
Cholelithiasis Cholelithiasis
Acute sickle hepatic crisis is best considered as the same
Budd-Chiari syndrome Coincidental chronic
pathophysiological process with a less severe clinical phe-
liver disease, e.g.,
notype. Reversal with supportive management, which
autoimmune
may or may not involve exchange transfusion, is the
Hepatic abscess/biloma
usual clinical course. Hepatic sequestration should be

TABLE 2. MANAGEMENT RECOMMENDATIONS IN SICKLE HEPATOPATHY

Clinical Scenario Clinical/Investigative Data Management Recommendations

Acute sickle hepatic crisis Vasoactive crisis Supportive exchange transfusion

RUQ pain/jaundice/"WCC
Bilirubin <15 mg/dL
ALT rarely >300 IU/L
Sickle cell intrahepatic Vasoactive crisis Full supportive management
cholestasis RUQ pain, leucocytosis, fever, Exchange transfusion
striking jaundice
Very high bilirubin
ALT can be in 1000s
Coagulopathy
Renal failure
Chronic cholestatic History of acute crises Longitudinal assessment
liver disease Chronic elevation in bilirubin Regular exchange transfusion
Exclude coincidental liver disease Ursodeoxycholic acid
End-stage chronic Often biliary-type cirrhosis Management of complications of cirrhosis
liver disease Sclerosing cholangitis-type injury reported Role of liver transplant not defined
Exclude coincidental liver disease
(e.g., autoimmune hepatitis)
Iron overload Elevated ferritin Chelation when liver iron
MRI for iron concentration concentration >7mg Fe/g dry weight
Viral hepatitis Chronic HBV Treatment as per normal guidelines
Chronic HCV Avoidance of ribavirin
Sickle gallstone Diagnosis by standard imaging techniques Cholecystectomy-prophylactic controversial
disease Pigment gallstones ERCP and duct clearance

Abbreviations: ALT, alanine aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; HBV, hepatitis B virus; HCV, hepatitis C
virus; MRI, magnetic resonance imaging; RUQ, right upper quadrant.

7 | CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD
REVIEW Sickle Cell Hepatopathy and Other Hematological Diseases Tavabie and Suddle
considered if there is a sudden drop in hematocrit associ-
ated with increase in liver size.
An important question that remains unanswered is
whether any specific intervention in the patient with
established chronic liver disease will modulate the risk for
progression to end-stage liver disease. We have used
ursodeoxycholic acid, and hydroxyurea if the patient has
frequent vasoactive crises and regular exchange transfu-
sion to maintain the sickle fraction less than (a somewhat
arbitrary) 40%. Chelation therapy should be considered
if indicated. The prevalence rate of cirrhosis in autopsy
studies has been between 16% and 29%.4 It is impor-
tant to exclude coincidental liver disease, especially
chronic viral hepatitis. For those with end-stage liver dis-
ease, the role for liver transplantation is gradually being
elucidated.5
ACUTE LEUKEMIA
Liver involvement is usually mild and clinically silent at
diagnosis. A slight elevation in alkaline phosphatase (ALP)
and mild-to-moderate hepatic enlargement may be
noted. Liver disease in these patients is more commonly
due to drug-induced hepatotoxicity, fungal infections
involving the liver, and posttransfusion chronic viral hepa-
titis. An exception is massive infiltration of the liver with
leukemic cells that can present as acute liver failure.6
CHRONIC LYMPHOID LEUKEMIA
Mild-to-moderate liver enlargement is common. Nodu-
lar regenerative hyperplasia (NRH) has been reported.
Functional impairment of liver function is usually a late
manifestation. NRH is classified among the causes of idi-
opathic noncirrhotic portal hypertension.7-9
CHRONIC MYELOID LEUKEMIA
At presentation, approximately 50% of patients have
mild-to-moderate hepatomegaly. In blastic phases of the
disease, liver enlargement increases because of infiltra-
tion by immature cells. Serum ALP also increases.9
MYELOMA
In multiple myeloma, mild-to-moderate hepatomegaly
is found in 15% to 40% of patients, sometimes accom-
panied by splenomegaly.10 Other manifestations of liver
8 | CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016
involvement are uncommon. Jaundice is rare, and amy-
loid deposition is very uncommon.
PRIMARY MYELOFIBROSIS11
Liver involvement is common. Hepatomegaly is present
in nearly all patients. Abnormal liver function tests are
present in 40% to 60% of patients. Splenomegaly is
common. Mechanisms of liver involvement, alone or in
combination, include extramedullary hematopoieses
(found in 90%-100% of patients), increased hepatic
blood flow, hemosiderosis (related to ineffective erythro-
poiesis or transfusion of blood product), or posttransfu-
sion chronic viral hepatitis. Portal hypertension develops
in a minority of patients (less than 10%). Potential causes
include NRH as a result of obstruction of intrahepatic
portal vein branches and increased hepatic vascular
resistance related to sinusoidal fibrosis and/or infiltration
by hemopoietic cells.11
OTHER CONDITIONS
Prothrombotic disorders and hematological disorders are
implicated in 80% of cases of Budd-Chiari syndrome and
more than 50% of noncirrhotic portal vein thrombosis.12
In patients with thalassemia, major liver disease is due to
iron overload and/or viral hepatitis acquired as a result of
transfusion of blood product. Chronic viral hepatitis is
common in patients with hemophilia who received clotting
factor concentrates before the availability of virus-
inactivated factors.12
SUMMARY
Sickle hepatopathy encompasses a wide variety of
hepatic pathology in patients with sickle cell anemia. The
spectrum of clinical phenotypes seen include asymptom-
atic abnormality of liver function, life-threatening acute
liver disease, and end-stage cirrhosis. Optimal manage-
ment requires close coordination with hematology col-
leagues. Liver involvement or disease is frequently
encountered in a number of other common hematologi-
cal conditions, as outlined earlier. A logical approach to
investigation and management again requires an under-
standing of the potential pathology caused by the hema-
tological condition itself or interventions used to treat
the condition.
An Official Learning Resource of AASLD
REVIEW Sickle Cell Hepatopathy and Other Hematological Diseases Tavabie and Suddle

5) Hurtova M, Bachir D, Lee K, Calderaro J, Decaens T, et al. Transplan-

CORRESPONDENCE
Abid R. Suddle, M.D., Institute of Liver Studies, King’s College Hospi-
tal, London, SE5 9RS, United Kingdom. E-mail: abid.suddle@nhs.net
tation for liver failure in patients with Sickle Cell disease: challenging
but feasible. Liver Transpl 2011;17:381-392.
6) Zafrani ES, Leclercq B, Vernant JP, et al. Massive blastic infiltration of the
liver: a cause for fulminant hepatic failure. Hepatology 1983;3:428-432.

REFERENCES 7) Garcia-Tsao G. Idiopathic noncirrhotic portal hypertension: what is

1) Gardner K, Suddle A, Kane P, O’Grady J, Heaton N, et al. How we
treat sickle hepatopathy and liver transplantation in adults. Blood
2014;123:2302-2307.
2) Banerjee S, Owen C, Chopra S. Sickle cell hepatopathy. Hepatology
2001;33:1021-1028.
3) Zakaria N, Knisely A, Portmann B, Mieli-Vergani G, Wendon J,
et al. Acute sickle cell hepatopathy represents a potential contra-
indication for percutaneous liver biopsy. Blood 2003;101:101-
103.
4) Berry PA, Cross TJ, Thein SL, Portmann BC, Wendon JA, et al.
Hepatic dysfunction in sickle cell disease: a new system of classifica-
tion based on global assessment. Clin Gastroenterol Hepatol 2007;5:
1469-1476.
it? Clin Liver Dis 2015;5:120-122.
8) Sweet DL, Golomb HM, Ultmann JE. The clinical features of chronic
lymphocytic leukaemia. Clin Haeamatol 1987;6:185-202.
9) Perez-Soler R, Esteban R, Allende E, et al. Liver involvement in multi-
ple myeloma. Am J Haematol 1985;20:25-29.
10) Pereira A, Bruguera M, Cervantes F, et al. Liver involvement at diag-
nosis of primary myelofibrosis: a clinicopathological study of twenty-
two cases. Eur J Haematol 1988;40:355-361.
11) DeLevel LD, Valla DC, Garcia-Tsoa. Vascular disorders of the liver.
Hepatology 2009;49:1729-1764.
12) Brugrera M, Miquel R. The effects of haematological and lymphatic
diseases on the liver. In: Textbook of Hepatology, Blackwell; 2007:
1662-1670.

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