1. The Liver in Sickle Cell Disease
Cage S. Johnson, M.D.
Professor Emeritus of Medicine and of Physiology and Biophysics
Director, Comprehensive Sickle Cell Center
Keck School of Medicine, University of Southern California,
Los Angeles, California, USA

2. HepatoBiliary Complications
hemolysis & accelerated bilirubin catabolism
Transfusion therapy
Vaso-occlusion
Disorders unrelated to the hemoglobinopathy
SS> SC> S-thalassemias

3. HepatoBiliary Complications:
Hepatomegaly
Hepatic ‘crisis’ (RUQ syndrome)
Hepatitis: viral, drug-induced, auto-immune
Hemosiderosis
Cholestasis: benign, progressive, drug-induced
Hepatic sequestration
Cirrhosis
Inspissated bile/Choledocholithiasis
Wide differential diagnosis

5. Hepatomegaly Increased blood volume and blood flow
Hepatocyte hyperplasia
Kupffer cell erythrophagocytosis, sinusoidal distention
Extra-medullary hematopoiesis
Passive congestion in right heart failure (pulmonary hypertension
Haematologia 22:169, 1989
Serjeant, 2001
Am J Med 69:833, 1980
Dig Dis Sci 31:247, 1986
J Pediatr Hematol Oncol 24:125, 2002

6. RUQ Syndrome RUQ pain, leucocytosis Jaundice: 3 to 12 mg/dL
fever, nausea, vomiting
Jaundice: 3 to 12 mg/dL
Variable elevation of AP & ALT
Lasting 2 days to 3 weeks
Differentiate from cholecytitis
Amer J Clin Pathol 44:1, 1965

7. Cent Afr J Med 40:342, 1994
J Trop Pediatr 34:59, 1988

8. Unusual causes of RUQ pain & abnl liver tests in Sickle Cell Disorders
Biloma
Focal nodular hyperplasia of the liver in children
Fungal ball
Hepatic artery stenosis
Hepatic infarct/abscess
Hepatic vein thrombosis
Mesenteric/colonic ischemia
Pancreatitis
Peri-colonic abscess
Pulmonary infarct/abscess
Renal vein thrombosis

9. RUQ syndrome Abdominal Examination Ultrasound Biliary scintigraphy:
high false positive rate [fasting, hepatocellular disease, chronic cholecystitis, extra-hepatic obstruction, narcotic-induced spasm of the sphincter of Oddi]
low positive predictive value but
high negative predictive value-patent cystic duct

10. N = 65: Hb SS - 6, Hb AS - 10, Hb AA (anemic) - 24, Hb AA - 25
Acute Viral Hepatitis
N = 65: Hb SS - 6, Hb AS - 10, Hb AA (anemic) - 24, Hb AA - 25
Peak bilirubin in Hb SS 4 x others; 40 mg/dL vs. 12 mg/dL
Hb SS 41 d vs. 25 to 38 d
AST, Alk P’tase, PT - no difference
Globulin persistently elevated in Hb SS
Degree of sickling on biopsy did not correlate with liver enzymes

12. Hepatology 19:1513, 1994

13. The Liver in Sickle Cell Disease
Hb SS, n=100: 78 elev. Ind. Bili only
Hb SC, n =25: 22 elev. Ind. Bili only
Hb SS
Hb SC
HBsAg + 3 1
HCV + 64 11
CLD 13
 Ind. Bili 6
Medicine (Balt) 64:349, 1985
Dig Dis Sci 31:247, 1986

14. Auto-immune Hepatitis
Painless jaundice & marked poly-clonal gammopathy
Positive ANA, SMA, LKM-1 or SLA/LP
Histology shows dense T-cell peri-potal infiltrates
Extra hepatic manifestions: arthropahty, rash, leg ulcers
Rx: prednisone/azathiprine for 24 months
Haematolgia 19:49, 1986
Am J Gastroenterol 91:1016, 1996
J Pediatr Hematol Oncol 19:159, 1997

16. Chronic Liver Diseases
Hb SS, n =22:
Cirrhosis with hemosiderosis - 5, Cirrhosis without hemosiderosis, Chronic active hepatitis B - 2, Drug-induced cholestasis - 2, chronic passive chogestion, and 1 each with elev. Alkaline phosphatase - bone, common duct obstruction, Histiocytic lymphoma, sarcoidosis, benign cholestasis of pregnancy, acute viral hepatitis B and five unexplained.
Hb SC, n = 3:
1 each with Alcoholic Liver Disease, granulomatous Hepatitis, unexplained.
Medicine (Balt) 64:349, 1985
Dig Dis Sci 31:247, 1986

17. Predictors of Liver diseaseX2
P <
Alb < 3.2 g/dL
2.2
.08
Glo > 4.0 g/dL
5.9
.05
Bili t > 4.0 mg/dL 28
.0001
Bili d > 0.5 mg/dL 8
.01
Alk Ptase > 225 IU 51
ALT > 100 IU 7
.015
ALT > 50 IU 22
AST > 100 IU 21
.0002
AST > 50 IU 16
Ferritin > 500 ng/mL 9
Ferritin > 300 ng/mL 10

18. Liver Histology Biopsy Autopsy n = 19 32 Sickling 17 30
Ischemc necrosis 1 14
Viral hepatitis 8 3
Miscellaneous 2 4
Other Disease
NSL 5 10
Dig Dis Sci 31:247, 1986

19. Hepatic Sequestration
Occurs about 1 per 161 admissions
Progressive enlargement of the liver with
falling hemoglobin
rising reticulocyte count
Markedly elevated bilirubin, predominantly conjugated fraction
Alkaline phosphatase as high as 650 IU
Modest elevation of transaminases [< 110 IU]
Obstruction of flow by vso-occlusion in small hepatic veins and/or sinusoids
Rx: exchange transfusion preferred
BMJ 294:1206, 1987
BMJ 290:744 & 1214, 1985
Postgrad Med J 72:487, 1996

20. Postgrad Med J 72:487, 1996

21. Am J Hematol 42:81, 1993

22. Br J Haematol 89:757, 1995

23. Blood 96:76, 2000

24. Blood 96:76, 2000

26. Cirrhosis Hepatitis B or C, auto-immune Hemochromatosis
Chronic passive congestion
Miscellaneous: alcohol, toxins, sarcoidosis, cryptogenic, chronic biliary obstruction

27. Summary
The majority of patients have only elevations of indirect bilirubin and LDH due to hemolysis
Chronic abnormalities in liver function are due to a wide variety of disorders other than the hemoglobinopathy. Judicious use of liver biopsy is often required for specific diagnosis.
Evidence for hepatitis B and C infection is common. Patients seropositive for hepatitis C have significantly greater serum globulin and transaminase levels than those seronegative.

28. Summary
Kuppfer cell erythrophagocytosis and intrasinusoidal sickling are universally found in hepatic histology and are not related to the degree of transaminase elevation. The absence of shrunken hepatocytes speaks against the concept of anoxic liver damage and is more consistent with the liver as the site of RBC destruction in the absence of splenic function.
The increasing use of transfusion therapy in this patient population is associated with a high frequency of trnasfusion transmitted viral disease and iron overload; prudence dictates ongoing surveillance for these and other liver disorders that may affect these patients.

30. Br Med J 295:234, 1987

31. N Engl J Med 307:798, 1982

33. J Pediatr 136:80, 2000

34. Gastroenterology 112:463, 1997