Revised January 10, 2001

Introduction

 

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 Hb SC and the S-thalassemia syndromes (Hb Sb⁰ thalassemia and Hb Sb⁺ thalassemia).
 

Methods

Literature review to the year 2000.

Cholelithiasis/Biliary Sludge

Chronic hemolysis with its accelerated bilirubin turnover leads to a high incidence of pigment gallstones. Ordinarily bilirubin levels in these patients do not exceed 4 mg/dL from hemolysis alone and the conjugated fraction is less than 10% (Johnson et al, 1985, West et al, 1992). The unconjugated bilirubin is substantially higher in patients with the UDP-glucuronyltransferase genetic defect of Gilbert's syndrome (Lin et al, Passion et al, 1999). Ultrasound surveys of patient populations indicate the onset of cholelithiasis as early as 2 to 4 years of age. Prevalence increases progressively with age (Sarniak et al, 1980, Walker et al, 2000), reaching a frequency of nearly 30% by 18 years of age.

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).

Acute and Chronic Cholecystitis

Fever, nausea, vomiting and abdominal pain are common events with a wide differential diagnosis, including hepatic, intestinal, pancreatic, vertebral, neurologic and pulmonary disroders (Table 1).
 

Table 1. Causes of abdominal pain reported in the sickling disroders

Abscess of total hip replacement Biloma Focal nodular hyperplasia Fungal ball Hepatic artery stenosis Hepatic infarct/abscess Hepatic vein thrombosis Interstitial nephritis Mesenteric/colonic ischemia Pancreatitis Peri-colonic abscess Pulmonary infract/abscess Renal vein thrombosis

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.

Cholecystectomy

Laparoscopic cholecystectomy on an elective basis in a well-prepared patient has become the standard approach to symptomatic patients. However, symptoms attributed to cholecystitis often persist after cholecystectomy. Because intra-operative cholangiography has a false positive rate estimated at 25%, ERCP at the time of laparoscopic cholecystectomy is preferred. However, IOC is still useful in delineating the anatomy of the cystic duct and its artery. The decision to proceed to cholecystectomy should be based on the natural history of the disorder in this patient population. The Jamaican data (Walker et al, 2000) provide the strongest argument for a conservative approach, but Jamaican patients seem to be substantially less symptomatic than those in North America. An aggressive approach provides the benefit of reducing the risk of the morbid complications of cholelithiasis, as well as eliminating gallbladder disease as a confounding item in the differential diagnosis of RUQ pain. For asymptomatic patients, the data support a conservative approach, but considerable controversy exists.

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.

Viral Hepatitis

Acute viral hepatitis has the same clinical course in the sickling disorders as in the general population, other than a higher peak bilirubin level reflecting baseline hemolysis.

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.

Other hepatitides

Autoimmune hepatitis has been reported in 5 patients (Chuang et al, 1997). The condition is acute in 30% of cases and has a 50% five-year mortality. This disorder is characterized histologically by dense T-cell infiltrates in the peri-portal areas with bridging fibrosis and piecemeal necrosis and by a marked polyclonal gammopathy. Extra-hepatic manifestations including arthropathy, rash and leg ulcers can occur. Treatment with plasma exchange has been successful. Prednisone and azathioprine given for 24 months induce a clinical remission initially, followed by biochemical then histological remission.

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.

Hemosiderosis/Hemochromatosis

Iron overload occurs with frequent transfusion, although one case report of genetic hemochromatosis exists. Measurement of hepatic iron stores with superconducting quantum interference device susceptometery is equivalent to biochemical measurement of tissue iron, but this instrument is available for research purposes at only one center in the U.S. Magnetic resonance imaging comparing the signal intensity of liver, pancreas and spleen to that of muscle is useful in the detection of iron overload but is not very sensitive to gradations of iron load. Decrease in signal intensity for the pancreas is a very useful index for hemochromatosis. The serum ferritin can be elevated out of proportion to the degree of iron stores reflecting its acute phase reaction property as well as other factors, such as ascorbate status or liver disease (Brittenham et al, 1993). The isotope, Ga-67 citrate, is carried by transferrin and may prove to be useful in the demonstration of iron overload but requires further study.

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.

Vascular occlusion

The hepatic complications attributed to vascular occlusion encompasses a variety of clinical syndromes for which our understandings of the relationships between clinical presentation, biochemical findings and histologic features remain unclear. The liver is generally enlarged throughout life, especially when adjusted for body size. The hepatic blood volume and blood flow are increased and, presumably, contribute to hepatomegaly. Liver histology invariably shows Kupffer cell hyperplasia with erythrophagocytosis, sinusoidal distension with aggregates of sickled erythrocytes and fine fibrosis in the space of Disse (Johnson et al, 1985 and Omata et al, 1986). The histologic features correlate poorly with the clinical status and amino-transferase level. The Kupffer cell erythrophagocytosis and sinusoidal aggregates likely reflect the site of hemolysis as evidenced by relatively low ISC counts in the hepatic vein and by the hepatic accumulation of red cell label in studies of RBC survival. However, massive distension of sinusoids has been described in syndromes of hepatic failure, implying an etiologic role for the severe degree of such findings.

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.

Hepatic sequestration

Acute hepatic sequestration is a rarely recognized complication of VOC; in one elegant study, there was one case in 161 hospital admissions (Davies and Brozovic, 1987). This syndrome is characterized by a rapidly enlarging liver accompanied by a decrease in hemoglobin/hematocrit and a rise in reticulocyte count. The liver is smooth and variably tender. The bilirubin may be as high as 24mg/dl with a predominance of the conjugated fraction. The alkaline phosphatase can be as high as 650 IU/L but can be normal. The transaminases are only minimally elevated and often are normal. Recurrence is common. Ultrasonography and CT scanning show only diffuse hepatomegaly. Liver biopsy shows massively dilated sinusoids with sickle erythrocytes and Kupffer cell erythrophagocytosis. Intrahepatic cholestasis with bile plugs in canaliculi can occur. Hepatocyte necrosis is unusual. The pathophysiology is believed to be obstruction of sinusoidal flow by the masses of sickled erythrocytes, trapping of red cells with within the liver and compressing the biliary tree. On the other hand, the pathophysiology could be similar to that suggested by ultrasonography in splenic sequestration, postulating obstruction at the smaller hepatic veins and/or sinusoids (Roshkow and Sanders, 1990). Undoubtedly mild episodes are not recognized.

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.

Cholestasis

Cholestasis can occur when the hepatic vein pressure abruptly increases, exceeding the maximal bile secretory pressure of 20-mm Hg, as seen in chronic passive congestion, Budd-Chiari syndrome or biliary obstruction. The phenomenon also results from with drugs that affect the Na⁺ K⁺ ATPase activity, such as phenothiazines, androgens, or estrogens, or with drugs like indomethacin that affect the bile-acid binding cytosolic proteins. In sepsis, endotoxin decreases bile flow. Acute and chronic cholestatic syndromes have been attributed to a wide variety of clinical entities in sickle cell patients.

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.
 

Summary of the state of the art

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.

Recommendations:

 
Biliary sludge is best managed by serial ultrasound examinations at 12 to 24 month intervals unless cholestasis occurs. At that point, laparoscopic cholecystectomy is indicated. Elective laparoscopic cholecystectomy has become the procedure of choice for symptomatic cholelithiasis (Jawad et al, 1998) because of the shorter hospital stay, lower cost and fewer immediate surgical complications. Watchful waiting, until symptoms dictate surgery is hte best option for asymptomatic (or minimally symptomatic) cholelithiasis. Bacteremia, ascending cholangitis, empyema and other hyper-acute biliary complications require surgery on a more urgent basis consistent with good surgical practice.

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.

Selected References: (alphabetical)

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.