Revised January 10, 2001
Liver and biliary tract dysfunction are common complications of sickle cell anemia and its variants. Early reports described jaundice, hepatic infarcts, acute and chronic viral hepatitis, choledocholithiasis, and cirrhosis. The pathophysiology of hepatic dysfunction was attributed to the classic histologic features of Kupffer cell erythrophagocytosis and engorgement of sinusoids by aggregates of sickled cells. More recent reports have emphasized the importance of hepatic disease as a consequence of conditions not necessarily related to hemoglobinopathy. Despite nearly 200 reports in the last 15 years on the hepato-biliary aspects of the sickling disorders, the frequency and pathophysiology of hepatic lesions remain unclear.
The hepato-biliary complications of the sickling disorders can be separated
into broad categories of disorders related to hemolysis, the problems of
anemia and transfusion management, the consequences of sickling and vaso-occlusion,
and defects unrelated to hemoglobin S. These complications of the sickling
disorders are most common in sickle cell anemia (Hb SS), but also occur
to a lesser extent in the doubly heterozygous sickle diseases, including
SC and the S-thalassemia syndromes (Hb Sb0
thalassemia and Hb Sb+ thalassemia).
The prevalence of cholelithiasis is substantially lower in African patients than in Jamaican or North American patients (Nzeh and Adedoyin, 1989). This difference is attributed to differences in dietary cholesterol and/or fiber but other factors (genetic or environmental) could have an influence. Xenobiotics such as the third generation cephalosporins can crystallize in the gall bladder and differences in the use of such antibiotics could account for some of the geographic variation in the frequency of cholelithiasis. The co-inheritance of alpha-thalassemia appears to reduce the frequency of stones by lowering the degree of hemolysis (Haider et al, 1998). The frequency of common duct stones is reportedly higher than in the general population. Common duct obstruction is frequently incomplete since pigment stones are small. They can produce the characteristic biochemical changes of cholestasis nonetheless. Gallstones can pass with or without pancreatitis.
Biliary sludge is a complex mixture of mucous, calcium bilirubinate and cholesterol in which hypersecretion of mucous leads to precipitation of bilirubin, forming a viscous material detectable by non-acoustic shadowing on ultrasonography (Lee et al, 1988). Biliary sludge may be an antecedent of gallstones. Certain antibiotics such as ceftriaxone seem to promote sludge formation. Studies in patients with sickle cell disease indicate that sludge is often found with stones, but sludge alone may or may not progress to stone formation. However, the period of follow-up of such studies is short (Al-Salem and Qaisruddin, 1998, Walker and Sarjeant, 1996).
Studies of gallbladder function indicate that those with cholelithiasis have larger fasting and post-prandial gallbladder volumes suggesting that stasis and incomplete emptying contribute to sludge and stone formation (Everson et al, 1989).
A careful clinical evaluation is necessary to establish a clear diagnosis. Biliary scintigraphy might be helpful, but its use is controversial because of a high false positive rate and low positive predictive value. However, it has a high negative predictive value since a normal study indicates that the cystic duct is patent. False positives can result from prolonged fasting, severe hepatocellular disease, extra-hepatic obstruction, chronic cholecystisis or narcotic-induced spasm of the sphincter of Oddi (Serafini et al, 1987). The Tc-99 RBC scan could possibly detect the hyperemia of acute cholecystitis, but its use has not been reported in these patients.
Treatment of acute cholecystitis does not differ from that of the general population and consists of antibiotics and general supportive care with consideration for elective cholecystectomy several weeks after the acute episode subsides.
The hepatic complications of the anemia are essentially those consequent to transfusion therapy with transmission of viral infection and the development of iron overload. As transfusion therapy is applied for an ever increasing number of indications, the risk for transmission of current and emerging infectious agents (HHV-8, HGV, TTV) needs continuing surveillance.
Surveys for serologic evidence of hepatitis B infection show a wide range of prevalence data related to the endemicity of the virus as well as to past transfusion practice (Johnson et al, 1985). In the general population, fulminant hepatitis occurs in 0.5%, with a high mortality, and chronicity is inversely related to age. Thus, vaccination seems indicated early in life; sickle cell patients respond as well as the general population.
Similar surveys for hepatitis C infection indicate that this infection is clearly related to transfusion practice and geographic endemicity and that chronic hepatitis mirrors the frequency in the general population (Hasan et al, 1996). In the general population, fulminant hepatitis is unusual, but as many as 65% will develop chronic hepatitis and cirrhosis. Chronic hepatitis is subtle, with only 25% of patients having AST/ALT as high as twice normal. In sickle cell disease, cirrhosis occurs, and liver transplants are now being done (Emre et al 2000). Chronic hepatitis C produces extra-hepatic manifestations that can confound the management of sickle cell disease. These manifestations include a cutaneous leucocytoclastic vasculitis and the picture of essential mixed cryoglobulinemia with purpura, arthralgias, glomerulonephritis, and peripheral neuropathy.
In studies of patients with persistent elevations of AST/ALT, biopsy invariably shows evidence of chronic hepatitis (Mills et al, 1988, Omata et al, 1986).
Treatment of chronic viral hepatitis is based upon the observation in the general population that sustained suppression of viral replication renders patients non-infectious, reduces the inflammatory process and slows the subsequent development of cirrhosis/hepatocellular carcinoma.
Indications for treatment of hepatitis B include HBsAg positivity for more than 6 months, HBV DNA positivity and persistent elevation of ALT and/or biopsy evidence for chronic hepatitis. Therapy consists of a -interferon, lamivudine, and/or famciclovir.
For hepatitis C, persistent elevation of AST/ALT, positive PCR for viral RNA and/or biopsy evidence of chronic hepatitis are indications for treatment with a -interferon plus ribivarin. Interferon also ameliorates the extra-hepatic manifestations related to the cryoglobulin.
Congestive heart failure, especially right-sided as seen in pulmonary hypertension, sepsis or shock can present with high AST/ASLT and a hepatitis-like picture. Centribular necrosis is often seen on biopsy.
The importance of iron overload is illustrated by studies of patients receiving transfusion for the prevention of stroke in whom the serum ferritin rose 10-fold at an average follow-up of 42 months and was associated with an eight-fold rise in AST/ALT (Harmatz et al, 200). In another study of women receiving supportive transfusion during pregnancy, incidental liver biopsy performed during abdominal surgery showed that two-thirds had significant hepatocyte iron accumulation after an average transfusion burden of 13.6 units (Yeomans et al, 1990).
Aggressive desferoxamine chelation with intravenous doses of 6 to 12 grams daily has been shown to provide better compliance than subcutaneous dosing, increases urine and fecal excretion several-fold, results in rapid decline in serum ferritin and ALT and is associated with clinical improvement in cardiac function and other indices. Adverse effects have not been noted in short-term therapy, although zinc excretion is increased (Silliman et al, 1993). A group of patients with ß-thalassemia major and near end-stage iron overload due to poor compliance were placed on aggressive chelation therapy when their attitudes toward compliance improved (Davis, et al., 2000). The patients improved remarkably during the 16-year period of follow-up, including in some instances reversal of severe congestive heart failure or cardiac arrythmias. Neither congestive heart failure nor cirrhosis should disqualify a patient from aggressive chelation therapy.
The "hepatic crisis" or right upper quadrant syndrome, consisting of right upper quadrant pain, fever, jaundice, elevated AST/ALT and hepatic enlargement is said to occur in as many as 10% of patients with acute vaso-occlusive pain. The AST/ALT fall rapidly differentiating this condition from the slower decline characteristic of acute viral hepatitis. In one study of 30 patients, liver tests taken at the time of uncomplicated VOC and four weeks later in the same steady-state showed that the alkaline phosphatase was 30% higher during VOC; ALT was three-fold higher, and bilirubin was elevated two-fold, primarily due to elevation of the conjugated fraction (Ojuawo et al, 1984). Treatment with supportive care is the only modality needed.
Abdominal pain presents a problem in differential diagnosis because of the wide variety of conditions with prominent abdominal pain reported in sickle cell disease (Table 1). Hepatic infarction occurs, with the characteristic wedge-shaped, peripherally located hypointense lesion on CT scan. Single or multiple abscesses have been described with an irregular shape on CT scan. Focal nodular hyperplasia of the liver has been seen with a characteristic avascular mass on angiography.
Successful resolution of hepatic sequestration has been seen with simple or exchange transfusion, as well as with supportive care alone. In one case, treated with simple transfusion, resolution of the sequestration was accompanied by a rapid increase in the circulating hemoglobin concentration, representing return of sequestered red cells to the circulation. Unfortunately, fatal acute hyperviscosity syndrome resulted (Lee and Chu, 1996). Because of this risk, exchange transfusion is preferred but careful monitoring is required.
Acute hepatic failure has been reported in several cases where massive hepatic necrosis was seen in the absence of markers for viral hepatitis. Exchange transfusion was followed by rapid improvement in clinical and biochemical features.
A benign cholestatic picture has been described in which there are striking elevations of bilirubin with only modest elevations of alkaline phosphatase and transaminases. Importantly, no impairment of hepatic synthetic function occurs, as reflected in the coagulation times (PT/PTT). The patients are asymptomatic with the exception of jaundice and/or pruritis. Fever, abdominal pain and gastrointestinal upset are conspicuously absent. Drug reactions are implicated in some cases, and measurement of anti-kidney/liver microsomal antibodies can assist in diagnosis. In all instances, resolution of cholestasis occurred within months in the absence of specific therapy (Buchanan and Glader, 1977, Johnson et al, 1985).
In contrast, progressive cholestasis in the absence of cirrhosis has
been reported in a small number of cases. These cases are characterized
by right upper quadrant pain, extreme elevation of bilirubin, striking
elevation of alkaline phosphatase and variable elevation of transaminases.
Importantly, renal failure, thrombocytopenia, and severely prolonged coagulation
times develop. Liver histology in both benign and progressive forms of
cholestasis shows intrasinusoidal sickling and Kupffer cell hyperplasia
with phagocytosis of sickled erythrocytes. Mortality due to uncontrollable
bleeding or to hepatic failure is common (Johnson et al, 1985, Shao
and Orringer, 1995). All survivors have been treated with exchange RBC
transfusion. Plasmapheresis with FFP, as well as platelet transfusion support,
have been used to control bleeding due to hemostatic failure.
Management of the hepato-biliary complications of the sickling disorders suffers from a dearth of systematic studies in these patients that clearly define the pathophysiology and consequent therapeutic approach. Data extrapolated from other patient populations provide the basis for treatment of cholelithiasis, hepatic abscess, acute and chronic hepatitis and iron overload. Anecdotal reports and small series generally support the approaches outlined here. Treatment approaches for those complications attributed to vaso-occlusion represent the opinions of experts in the field taken from case reports.
The management of chronic hepatitis is beyond the scope of this treatise but requires close coordination with gastroenterology and the judicious use of liver biopsy to guide diagnosis and therapeutic decision making.
Iron overload can be managed by the standard subcutaneous protocols, but the intensive intravenous approach is attractive because of the claim of improved compliance (Silliman et al, 1993).
The syndromes attributable to intra-hepatic vaso-occlusion seem best treated with exchange RBC transfusion because of the remote risk of acute hyperviscosity (Lee and Chu, 1996). Plasmapheresis and platelet transfusion support are useful in cases associated with hemostatic failure.
Brittenham GM, Cohen AR, McLaren CE et al : Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Amer J Hematol 1993;42:81-85.
Buchanan GR, Glader BE: Benign course of extreme hyperbilirubinemia in sickle cell anemia: Analysis of six cases. J Pediatr 91:21-24, 1977.
Chuang E, Ruchelli E, Mulberg AE: Autoimmune liver disease and sickle cell anemia in children: A report of three cases. J Pediatric Hematol oncol 1997;19:159-162.
Davies SC, Brozovic M: Acute Admissions of patients with sickle cell disease who live in Britain. Br Med J 1987;294:1206-1208.
Emre S, Kitibayashi K, Schwartz M, et al : Liver transplantation in a patient with acute liver failure due to sickle cell intrahepatic cholestasis. Transplantation 2000;69:675-676.
Everson GT, Nemeth A, Kourourian S, et al:: Gallbladder function is altered in sickle hemoglobinopathy. Gastroenterology 1989;96:1307-1316.
Haider MZ, Ashebu S, Aduh P, Adekile AD: Influence of a -thalassemia on cholelithiasis in SS patients with elevated Hb F. Acta Haematol 1998;100:147-150.
Harmatz P, Butensky E, Quirolo K et al : Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 96: 76-79, 2000.
Hasan MF, Marsh F, Posner G et al:: Chronic hepatitis C in patients with sickle cell disease. Am J Gastroenterology 1996;91:1204-1206.
Jawad AJ, Kurban K, El-Bakry A, Al-Rabeeah A, Seraj M, Ammar A: Laparoscopic cholecystectomy for cholelithiasis during infancy and childhood: cost analysis and review of current indications. World J Surg 1998;22:69-74.
Johnson CS, Omata M, tong MJ, Simmons, Jr. JF, Weiner J, Tatter D: Liver involvement in sickle cell disease. Medicine (Baltimore) 1985;64:349-356.
Lee ESH, Chu PCM: Reverse sequestration in a case of sickle cell crisis. Postgrad Med J 72:487-488, 1996.
Lee SP, Mather K, Nicholls JF: Origin and fate of biliary sludge. Gastroenterology 1988;94:170-176.
Lin J, Johnson CS, Liebman HA: Gilbert's syndrome in sickle cell anemia. Annual Meeting of the National Sickle Cell Disease Program, Washington, DC, September 15-20, 1997.
Mills LR, Mwakyusa D, Milner PF: Histopathologic features of liver biopsy sepcimens in sickle cell disease. Arch Pathol Lab Med 1988;112:290-294.
Nzeh DA, Adedoyin MA: Sonographic pattern of gallbladder disease in children with sickle cell anemia. Pediatric Radiol 1989;19:290-292.
Ojuawo A, Adedoyin MA, Fagbule D: Hepatic function tests in children with sickle cell anemia during vaso-occlusive crisis. Cent Afr J Med 1994;40:342-343.
Omata M, Johnson CS, Tong MJ, Tatter D: The pathological spectrum of liver diseases in sickle cell disease. Dig Dis Science 1986;31:247-256.
Passon RG, Howard TA, Zimmerman SA, Schultz WH, Ware RE: The effect of UDP-gluconosyltransferase (UGTIA) promoter polymorphisms on serum bilirubin levels and cholelithiasis in patients with sickle cell anemia. Blood 1999;94 (suppl):645a.
Davis BA, Porter JB: Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood 2000 Feb 15;95(4):1229-36
Roshkow JE, Sanders LM: Acute splenic sequestration crisis in twoadults with sickle cell disease: US, CT, and MR imaging findings. Radiology 1990;177:723-725.
Sarnaik S, Slovis TL, Corbett DP, Enami E, Whitten CF: Incidence of cholelithiasis in sickle cell anemia using the ultrasonic gray-scale technique. J Pediatric 1980;96:1005-1008.
Serafini AN, Spoliansky G, Sfakianakis N, Montalvo B, Jensen WN: Diagnostic studies in patients with sickle cell anemia and acute abdominal pain. Arch Intern Med 1987;147:1061-1062.
Shao SH, Orringer EP: Sickle cell intrahepatic cholestasis: Approach to a difficult problem. Amer J Gastroenterology 1995;90:2048-2050.
Silliman CC, Peterson VM, Mellman DL, Dixon DJ, Hambridge KM, Lane PA: Iron chelation by desferoxamine in sickle cell patients with severe transfusion-induced hemosiderosis: A randomized double-blind study of the dose-response relationship. J Lab Clin Med 1993;122:48-54.
Walker TM, Hambleton IR, Serjeant GR: Gallstones in sickle cell disease: Observations from the Jamaican cohort study. J Pediatric 2000;136:80-85.
Walker TM, Serjeant GR: Biliary sludge in sickle cell disease. J Peditr 1996;129:443-445.
West MS, Wethers D, Smith J, Steinberg M and the Cooperative Study of Sickle Cell Disease: Laboratory profile of sickle cell disease: A cross-sectional analysis. J Clin Epidemiol 1992;45:893-909.
Yeomans E, Lowe T, Eigenbrodt EH, Cunningham FG:
Liver histopathologic findings in women with sickle cell disease given
prophylactic transfusion during pregnancy. Am J Obstet Gynecol 1990;163:958-964.