StemCell Therapy

Sickle cell disease affects the hepatobiliary system in different ways at different ages. Intrinsic disease results from recurrent ischemia and bilirubin stones. These result from the vascular obstruction and red cell hemolysis of sickle cell. Biliary sludge is a common finding that is often clinically unimportant. Viral infections that affect the liver may be independent of or secondary to red cell transfusions. The iron overload that accompanies red cell transfusions can lead to liver dysfunction and fibrosis. Many medications taken by sickle cell patients may cause or worsen hepatobiliary disease. The dysfunction of the liver can affect the lungs, kidneys, and coagulation systems. Treatment is directed at the etiology of the dysfunction as well as the underlying sickle cell disease.

The natural consequences of any hemolytic condition affect both the gallbladder [45] and the liver [46]. The gallbladder is affected by hemoglobin (pigmented) stones [47], biliary sludge [4850], and obstruction [5153]. The liver is affected by vasoocclusive changes (right upper quadrant syndrome) of recurrent ischemia and reperfusion injuries [46, 54], iron overload from transfusions that are used to treat both symptomatic anemia and the complications of sickle cell disease [5559], vascular endothelial dysfunction [60], and the liver consequences of the hypercoagulation of sickle cell [6163].

The challenge physicians caring for sickle cell patients is recognizing the life-threatening course from the more frequent, similar appearing milder, recurrent syndromes. A useful way to consider the protean effects of hepatobiliary issues in sickle cell is to consider the disorders of the presentation and evaluation of abdominal complaints of sickle cell followed by a review of the major disorders. Although hepatobiliary conditions are intimately linked, the embryology of the biliary system and the hepatic system shows these two organs to be histologically and functionally separate [64]. This explains the differential response of these organs to the same insult. However, many conditions may overlap, so a single diagnosis may mask parallel processes.

Acute pain in the right upper quadrant is common in sickle cell patients [6567]. The symptom of hepatobiliary disease often must be separated from the more common symptoms of sickle cell disease. Patients develop sickle cell attacks in a consistent pattern. The patient can often recognize whether the current attack is different from prior sickle cell pains. If the pain is new, especially when accompanied by more jaundice than usual, nausea and vomiting, then further hepatobiliary workup is needed. Increasing nausea and vomiting with food points to the gallbladder. Colic pains point to the gallbladder. Right upper quadrant fullness with dull pains points to the liver. General jaundice points to both.

The liver is often increased in size throughout the life of the patient [68]. If the liver has acutely increased in size, then hepatic congestion or sequestration may be involved. A 1980 clinicopathologic study of 70 autopsies of sickle cell patients found 91% with enlarged livers characterized by distention of Kupffer cells engorged with red cells [69]. In 27% the liver sinusoids were distended with obstruction from sickled red cells. Focal necrosis of liver tissue was present in 34%. 20% of patients had reparative liver changes of portal fibrosis and regenerative nodules. The authors felt that recurrent vascular obstruction, ischemia, necrosis, and repair best explained the pathological findings.

If right upper quadrant pain is severe, then acute swelling or inflammation may be involved. Murphy's sign is often lost in the general pains but, if present, may point to the gallbladder. If the serum bilirubin concentration is over 4mg/dL, then checking whether the fraction of direct bilirubin exceeds 10% would point to the gallbladder as the source of the increase [70, 71]. Some patients have genetic variations in the UDP glucuronyltransferase that will elevate the serum bilirubin concentration [72]. This recurrent or chronic elevation should be evident on review of the patient's records. In most sickle cell presentations the AST is relatively more elevated that the ALT, as the AST also reflects the degree of hemolysis [73]. If the ALT is similarly elevated as the AST, then a hepatocellular process may be occurring. Similarly the alkaline phosphatase will be elevated in biliary disease. However, bone infarcts will also call the alkaline phosphatase to rise. Fractionating the alkaline phosphatase into bone and biliary sources is seldom done. The clinical presentation usually finds bone pain or severe extremity pains with infarcts, and severe right upper quadrant pains prompt imaging, usually ultrasound, of the hepatobiliary system. Measurement of the aPPT and PT may provide evidence of a more severe process beginning.

Initial evaluation is for conditions that need emergent transfusions or treatments.

Pain patterns that differ from a patient's usual pattern need close evaluation.

Having sickle cell does not protect a patient from any other condition.

Hepatic crisis is often used as a general term to describe right upper quadrant pain in a sickle cell patient [80, 81]. However, hepatic crisis is best used to describe a syndrome consisting of pain, elevated ALT (usually less than 300IU/liter), and hepatic enlargement. Another working definition of a hepatic crisis could be painful hepatomegaly and worsened jaundice (usually less than 12mg/dL) [82]. The definition used causes the incidence of this condition to vary in reports. Large series reports that up to 10% of patients admitted to hospital have hepatic involvement rising to their definition of crisis. Other studies with more restrictive definitions concluded hepatic crisis was rare. The rapidity of the onset of symptoms and the rapidity of the correction of ALT may be able to guide therapy. Symptoms that began suddenly are more often typical, self-limited sickle cell conditions. Symptoms that begin over several days to weeks may be from more severe conditions such as viral or autoimmune hepatitis, liver infarct, or gallbladder dysfunction. Severe elevations of bilirubin (over 30mg/dL) may represent acute liver failure of intrahepatic cholestasis (see below).

If the condition is from typical sickle vaso-occlusion and inflammation, then the elevation of ALT decreases after a few days. Severe, persistent elevations may relate to hepatic infarct, characterized by a wedge-shaped, hypointense CT lesions [83]. Hepatic abscess has been rarely reported, but should be suspected in a patient with fever, a course different from their usual sickle cell crisis, right upper quadrant pain, and tender hepatomegaly [8488]. Hepatic ultrasound would delineate the abscess. Prior areas of hepatic infarction give the bacteria a site to invade. Bacteroides species were found in one report [85]. Bilirubin levels decrease to prior values in about two weeks; liver transaminases return to prior values in about three months. If changes persist beyond those times, further evaluation is needed.

Hepatic sequestration is best diagnosed by a rapid enlargement of the liver with a concurrent drop in hemoglobin concentration [8991]. The bilirubin also will be elevated with a high percentage of direct bilirubin. Transfusions, simple or exchange, may help reserve the process. Hepatic sequestration may be a life-threatening event in pediatric patients with sickle cell disease [8991]. Small vessel congestion with red cells leads to a drop in hemoglobin levels. The liver enlarges and becomes tender and inflamed. Treatment is transfusions. Often the hemoglobin level is low enough that given red cell units (matched for ABO, Kell, E, and C antigens) to raise the hemoglobin to 9g/dL often stabilize the process. Manual or automatic red cell exchanges are indicated for more severe cases shown by hepatic dysfunction or a hemoglobin level over 9 to start with. Hepatic sequestration may be part of the multiorgan failure syndromes [74, 75].

Chronic hepatic sequestration has been reported in a 17-year old with SS hemoglobin [92]. After exchange transfusions, his liver size decreased. However it recurred. This recurrence was successfully treated with hydroxyurea for several months.

One report of reverse sequestration occurred following simple transfusions. This syndrome comprises a sudden increase in hemoglobin concentration, sudden onset of hypertension, acute congestive heart failure, neurologic signs of infarct or hemorrhage [93].

Autoimmune hepatitis is reported in sickle cell patients [94, 95]. Interestingly, it also appears in mice models of sickle cell disease (personal communication). We have documented transient positivity of antibodies to smooth muscle (antiactin F). Associated features of autoimmune hepatitis include rashes, skin ulcers, and joint disease. The etiology, natural course, and treatment of autoimmune hepatitis in sickle cell patients are unclear. If a patient has persistent liver symptoms and antibody titers to smooth muscles, then a therapeutic trial of prednisone and azathioprine may be warranted. Referral to a hepatologist is indicated.

Viral hepatitis occurs at least as frequently as in the general population [96]. Hepatitis C, and to a lesser extent, Hepatitis B, occurred more often because of blood product exposure. Improved blood product testing has reduced the incidence of these infections, but they still occur. We screen all our patients yearly for Hepatitis C viral RNA by PCR. In new patients, persistently elevated ALT levels require screening for viral hepatitis. Every sickle cell patient should be vaccinated with two doses of Hepatitis A vaccine from six months to a year apart and three doses of Hepatitis B vaccinations at zero, one, and six months. Quantitative hepatitis B surface antibody tests and total Hepatitis A antibody tests are available to help decide if a patient has been adequately vaccinated if the records are not available. Many practitioners opt to revaccinate in case of any doubt. No vaccine exists for Hepatitis C prevention. Patients with chronic Hepatitis B and Hepatitis C should be treated as any other patients. There has been some concern about using ribavirin because it may cause hemolytic anemia. If a patient on ribavirin does develop worsening anemia, then placing the patient on monthly transfusions would both allow therapy to continue and would decrease sickle cell and anemia symptoms. A recent article showed good results in treating sickle cell patients for chronic hepatitis C [97]. Liver transplants are as successful in patients with sickle cell disease and other patients needing allographic livers [98101].

Hepatic siderosis is a growing area of concern and research [102]. As red cell transfusions become routine for more indications, the inevitable result is the accumulation of liver iron. After about a year of transfusion therapy, serum ferritin levels rise to over 1,000ng/mL. While serum ferritin is a rough guide to total liver iron, values over 1,000 indicate liver iron overload. Other studies have shown significant liver iron accumulation after 13 units of red cells. Each unit of red cells contains nearly a year worth of dietary iron. Over many years, hepatic dysfunction, insufficiency, fibrosis, and cirrhosis may lead to morbidity and even liver death. Many patients on regular transfusions will have hyperintense livers on CT scans or hypointense livers on MRI scanning [103, 104]. These changes have been used to semiquantitate the degree of iron loading. Chelation with deferoxamine [55, 105], deferasirox [106], or deferiprone (recently approved in the US) does reduce total body iron. However, all regimes have issues with compliance and side effects that require appropriate monitoring. When patients with iron overload are admitted to hospital with noninfectious complaints, we often give deferoxamine 3 grams in 500mL normal saline intravenously over 24 hours, repeating continuously during their stay. Giving Vitamin C 250mg orally daily while the patient is on deferoxamine increases iron excretion [107, 108]. Ongoing cohort studies should help define the natural history of iron overload in sickle cell patients [109111].

Hepatic effects on kidneys and lungs are increasingly recognized. Although there are few publications concerning sickle cell patients, such effects are well known in other conditions where the liver is cirrhotic or dysfunctional. The hepatorenal syndrome [112], hepatopulmonary syndrome [113], and the portopulmonary [114] syndrome may complicate the hepatic disease of sickle cell.

Sickle cell intrahepatic cholestasis or sickle cell hepatopathy is a condition with marked hyperbilirubinemia (>50mg/dL) and a high fraction of direct (conjugated) bilirubin (about 50%) [77, 115118]. Other features of right upper quadrant pain and progressive hepatomegaly resemble many of the hepatic crisis syndromes. However, in sickle cell intrahepatic cholestasis, the liver transaminases are nearly at baseline. Coagulopathy as assessed by the PT test is often found. Renal insufficiency is often present, likely from the nephrotoxic effects of bilirubin. Endoscope retrograde cholangiopancreatography has been reported to guide management by diagnosing strictures from ischemic cholangiopathy and defining the presence or absence of common bile duct stones [119]. Some authors consider the presence of acute sickle hepatopathy to contraindicate liver biopsies [120]. Ischemic cholangiopathy has also been described [121].

Early reports indicate that sickle cell intrahepatic cholestasis was a life-threatening condition that mandated exchange transfusions. As clinicians were more aware of the condition, series were reported that had a less severe course [122]. Given the protean causes of intrahepatic cholestasis, it is reasonable to divide cases of cholestasis into those with and those without other evidence of marked hepatic dysfunction and coagulopathy. The milder cases (bilirubin level 10 to 30mg/dL) appear to be more common in children. Patients in the first category should be monitored for worsening hepatic function: encephalopathy, coagulopathy, and rising bilirubin concentrations. For the more severe cases, exchange transfusion may be given, but it is not always effective [77, 79].

Cholelithiasis occurs as early as two years old [47]. About 30% of patients will have gallstones by 18 years of age [52, 123, 124]. The incidence and prevalence of this condition appears to be affected by local diet and possible genetic factors [125]. The coinheritance of -thalassemia may reduce the incidence of stones since it may lessen the degree of hemolysis that is thought to drive stone formation [126]. The cause of cholelithiasis is usually pigmented stones resulting from the breakdown of hemoglobin [45]. Some reports implicate ceftriaxone and other third generation cephalosporins as causing crystallization in the gallbladder [127]. However, these antibiotics are commonly and usefully used in the proper settings. In adults, asymptomatic gallstones are common and are best treated by observation only [52, 53, 68, 123]. Abdominal and right upper quadrant pains are common in sickle cell patients. Cholecystectomy for recurrent right upper quadrant pains often does not relieve the recurrent symptoms. Only if signs of cholecystitis (fever, increased direct bilirubin, and positive imaging) develop, should cholecystectomy be considered after the treatment with supportive care and antibiotics [47, 124]. Laparoscopic cholecystectomy is the procedure of choice for this indication [128, 129]. This also causes less abdominal muscle disruption and decreases postsurgical complications including acute chest syndrome. Ultrasound is the imaging of choice but is not diagnostic in most cases. Reports of pancreatitis from sickling also exist. Biliary scintigraphy is seldom used because of the numerous false positive results [130, 131]. Still, it has a useful negative predictive value if used in the right setting. Technetium scanning may show hyperemia of cholecystitis but its use is not well studied. Liver peliosis and extramedullary erythropoiesis have occasionally been noted as multiple nodules on liver imaging [132].

Biliary sludge is a common finding in sickle cell patients [48, 50]. Biliary sludge is nonshadowing, echogenic intraluminal sediment. This material is calcium bilirubinate, cholesterol crystals, viscous bile, mucus, and proteins. The natural history of biliary sludge in children with sickle cell disease finds that at a mean of 2.1 years of followup, about 65% of such patients do eventually develop gallstones, although not necessarily symptomatic ones. About 40% of patients originally with biliary sludge do not develop gallstones, despite the continued presence of sludge in most [133]. Most authors recommend yearly ultrasounds to access stone formation. They reserve cholecystectomy only for patients with signs and symptoms of acute cholecystitis [133].

Choledocholithiasis also occurs in sickle cell disease [51]. Even in patients with cholecystectomy, recurrent stones may form in the common bile ducts. Symptoms are similar to primary gallbladder disease. Ultrasound may be the best modality to evaluate the common bile duct. Duct obstruction is seldom complete. This may be because pigmented stones are smaller than nonpigmented stones. If the common duct is obstructed, then symptomatic or chemical pancreatitis may be the presentation [134]. After cholecystectomy, the common bile duct is usually dilated, confounding diagnosis of new stones. Given the prevalence of common duct stones, patients with persistent cholestatic jaundice should have imaging to evaluate the ductal system. If surgery is contemplated, some authors suggest ERCP as the best approach to determine management [135].

Acute cholecystitis presents as it does in patients without sickle cell disease [53, 136]. Right upper quadrant pain, fever, nausea, and vomiting have a long and diverse differential diagnosis. When the diagnosis is suspected, then ultrasound is the usual next step. Imaging signs of acute inflammation or obstructing stones prompt treatment for pain, hydration, and the assessment for infection. Laparoscopic cholecystectomy is deferred until the acute episode is over. If all the stones and sludge have cleared, then surgery may not be indicated. Some authors prefer a conservative approach. Intraoperative cholangiography is reported to have a 25% false positive rate. Some authors recommend intraoperative ERCP. A detailed intraoperative evaluation of the biliary system is important as symptoms often persist or recur after cholecystectomy [124].

Chronic cholecystitis may be related to persistent gallstones or persistent biliary sludge. Recurrent symptoms consistent with colic warrant screening with blood work and imaging. If the blood work shows increases in conjugated (direct) bilirubin during the attacks, and there are ultrasonographic signs of a thickened gallbladder wall, then cholecystectomy may decrease these symptoms. However, just as in chronic cholecystitis in the general population, the symptoms may recur several months after surgery.

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