Lymphoma and hematological conditions: II. Sickle cell hepatopathy and other hematological diseases

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Abbreviations

ALP

alkaline phosphatase

ALT

alanine aminotransferase

ERCP

endoscopic retrograde cholangiopancreatography

HBV

hepatitis B virus

HCV

hepatitis C virus

MRI

magnetic resonance imaging

NRH

nodular regenerative hyperplasia

RUQ

right upper quadrant

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 HbSβ‐thalassemia. Liver disease can result directly from the effects of sickling within the liver, from complications related to the multiple blood transfusions some patients require, or be coincidental. 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.

Table 1.

Classification of Sickle Hepatopathy

Acute Liver Disease	Chronic Liver Disease
Related to Sickling Process
Acute sickle hepatic crisis	Chronic cholestasis
Hepatic sequestration	Biliary‐type cirrhosis
Sickle intrahepatic cholestasis
Related to multiple blood transfusion
Viral hepatitis B and C	Chronic viral hepatitis
Miscellaneous
Cholelithiasis	Cholelithiasis
Budd‐Chiari syndrome	Coincidental chronic liver disease, e.g., autoimmune
Hepatic abscess/biloma

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 especially in the acute liver syndromes, and should be considered only if results will materially affect management. This is not usually the case. The evidence basis for medical treatments is not strong. There is a need for good‐quality, prospective studies to define natural history and provide evidence for specific interventions.

Recommendations regarding management of the specific clinical syndromes encompassed within sickle hepatopathy are listed in Table 2. Sickle cell intrahepatic cholestasis is a severe acute presentation and is often fatal. It is thought to be as a consequence of widespread sickling within the sinusoids, with resultant ischemia and hepatocyte injury. Striking jaundice can develop (levels of up to 270 μmol/L or 15 mg/dL have been reported) in association with renal failure and coagulopathy. Full supportive management is instituted, and there is some evidence for the use of vigorous exchange transfusion. Acute sickle hepatic crisis is best considered as the same pathophysiological process with a less severe clinical phenotype. Reversal with supportive management, which may or may not involve exchange transfusion, is the usual clinical course. Hepatic sequestration should be considered if there is a sudden drop in hematocrit associated with increase in liver size.

Table 2.

Management Recommendations in Sickle Hepatopathy

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

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 transfusion 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 important to exclude coincidental liver disease, especially chronic viral hepatitis. For those with end‐stage liver disease, 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 hepatitis. 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. Nodular regenerative hyperplasia (NRH) has been reported. Functional impairment of liver function is usually a late manifestation. NRH is classified among the causes of idiopathic noncirrhotic portal hypertension.7, 8, 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 infiltration 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 accompanied by splenomegaly.10 Other manifestations of liver involvement are uncommon. Jaundice is rare, and amyloid 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 erythropoiesis or transfusion of blood product), or posttransfusion 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 asymptomatic abnormality of liver function, life‐threatening acute liver disease, and end‐stage cirrhosis. Optimal management requires close coordination with hematology colleagues. Liver involvement or disease is frequently encountered in a number of other common hematological conditions, as outlined earlier. A logical approach to investigation and management again requires an understanding of the potential pathology caused by the hematological condition itself or interventions used to treat the condition.