Abnormal Liver Function Tests

Abnormal liver function tests (LFTs) have been reported to occur in > 40 and 80% of patients in the first year after autologus or allogeneic SCT, respectively. Many individuals have abnormal LFTs prior to transplantation, as a result of previous chemotherapy. In addition, iron overload is commonly found among SCT patients as a result of increased red cell turnover and multiple blood transfusions. Chronic viral hepatitis B or C may also be identified prior to transplantation. Although the pattern of elevation can help distinguish between cholestatic liver disease and hepatitis, often the etiology is ambiguous without a liver biopsy. Despite the increased risk of bleeding in SCT patients, we advocate the use of transjugular liver biopsy whenever withdrawal of potentially hepatotoxic medications fails to improve LFT abnormalities. The transjugular liver biopsy, using a retractable Tru-Cut needle, is best performed by a skilled interventional radiologist. This approach is preferred over the percutaneous approach, which disrupts the hepatic capsule and may be complicated by subcapsular hematoma or a peritoneal bleed in these patients who have coagulopathies.

Veno-occlusive Disease

In the first 3 weeks following SCT, liver function abnormalities raise the possibility of veno-occlusive disease (VOD). VOD has been reported to occur in up to 20% of allogeneic and 10% of autologous transplantation recipients and is the most likely cause of new ascites that arises in the immediate post-transplantation period. Late-onset ascites is rare, and a diagnostic paracentesis will aid in distinguishing portal hypertension secondary to chronic liver disease, metastatic carcinoma, or myxedema ascites.

Preexisting liver disease is the major risk factor for the development ofVOD. The diagnosis ofVOD should be entertained if there are LFT abnormalities, ascites or a 10% increase in body weight, and hepatomegaly (Table 48-1). In the immediate post-transplantation setting, Doppler ultra-sonography will demonstrate decreased or retrograde flow in the portal vein. A hepatic resistive index > 0.76 is highly suggestive of VOD, but its calculation is not particularly sensitive (Teefey et al, 1995). Although the Seattle or Baltimore VOD clinical criteria have a sensitivity and specificity > 88%, a transjugular liver biopsy with measurement of hepatic vein gradient is the best way to confirm the diagnosis. Hepatic injury occurs in zone 3 with subendothelial edema, sinusoidal congestion, hepatic venule occlusion, and hepatocyte necrosis. Severe VOD is accompanied by fibrous narrowing or terminal hepatic venules and widespread hepatocellular necrosis. VOD may result in fulminant hepatic failure, characterized by dramatic rises and falls in the serum transami-nases, accompanied by prolongation of the prothrombin time

TABLE 48-1. Clinical Criteria for Veno-occlusive Disease

Baltimore Criteria (Jones et al, 1987) Jaundice and any two of the following: Ascites

Weight gain > 5% baseline Hepatomegaly

Seattle Criteria (any two prior to day 20) (McDonald et al, 1993) Jaundice

Ascites ± unexplained weight gain of > 2% baseline Painful hepatomegaly and the development of hepatic encephalopathy. The prognosis is grim, but survivors may develop a nodular appearing liver, composed of regenerated liver nodules. The collapse of hepatic parenchyma may result in fibrosis and eventual portal hypertension. Transjugular intrahepatic portosystemic shunting has been attempted (Azoulay et al, 1998), as has successful orthotopic liver transplantation in patients who are free of malignancy (Rapoport et al, 1991). Therapy directed at the underlying VOD has yielded mixed results. Heparin and tissue plasminogen activator have limited efficacy and have been associated with serious bleeding complications. The experimental use of intravenous difibrotide, a poly-deoxyribonucletide with antithrombotic and fibrinoytic effects, shows potential promise in treating severe VOD, particularly in younger patients (Richardson et al, 2002). In one randomized, placebo-controlled study of allogeneic SCT recipients, administration of prophylactic ursodiol was associated with a decreased incidence of VOD (Essell et al, 1998), but no improvement in VOD incidence was observed in a more recent study by another group (Ruutu et al, 2002).

GVHD

Hepatic GVHD has two clinical presentations. Most often, cholestatic LFT abnormalities occur. This reflects the direct injury of bile duct cells by donor white blood cells. Liver biopsy is critical for making the diagnosis. Even in patients with skin and/or gut GVHD, hepatic abnormalities have many etiologies, and without a biopsy it cannot be assumed they are due to GVHD. A liver biopsy should be considered in such patients whose LFTs fail to improve in response to therapy in a manner commensurate with skin or gut improvement. Liver histology is characterized by focal or widespread bile duct epithelial injury with varying degrees of portal lymphocytic infiltration. These findings are often accompanied by interlobular bile stasis. Less commonly, usually in the setting of a donor lymphocyte infusion, an atypical lobular hepatitis occurs, with transaminases rising in some cases to > 10 times normal (Akpek et al, 2002). Treatment of GVHD is usually done at the recommendation of the transplantation center, with initial therapy usually involving high dose corticosteroids. Hepatic GVHD may progress to cirrhosis and portal hypertensive complications. In a randomized open-label study, prophylactic ursodiol administration (600 to 900 mg every day) reduced the incidence of severe GVHD and improved survival (Ruutu et al, 2002).

TPN-Associated Cholestasis

Abnormal LFTs may arise as the result of TPN (Angelico and Guardia, 2000). Hepatic steatosis is a common finding even 5 days after the initiation of TPN and results from an excess of calories in the form of carbohydrates. Intrahepatic cholestasis is typified by the presence of an inflammatory periportal infiltrate and bile duct plugging. It may progress to biliary cirrhosis.An excess of lipid calories (> 50% of total calories) or bacterial translocation across the gut wall with resulting cytokine release are among the etiologies proposed. Ursodiol (Actical) 300 mg 3 times daily has been used to treat TPN-induced intrahepatic cholestasis but no randomized placebo-controlled studies have been reported. A controlled, open-label study to determine if taurine conjugated ursodeoxycholic acid (30 mg/kg/d) would protect against cholestasis in infants showed no difference in LFT abnormalities (Heubi et al, 2002).

Cholestasis of Sepsis

SCT patients are at high risk for infection due to eradication of their bone marrow and treatment with immuno-suppressive drugs to control GVHD. Sepsis may be associated with profound pro-inflammatory cytokine release in response to bacterial lipopolysaccharide (Gilroy et al, 2003). Cytokines, such as tumor necrosis factor-a, interleukin 1-p, and interleukin-6, appear to interfere with sinusoidal bile transport giving rise to cholestasis. Typically there are elevations of the total bilirubin out of proportion to other LFTs. Although most commonly associated with gram-negative infections, almost any type of organism can cause the cholestasis of sepsis. The etiology is established usually by temporal correlation with other symptoms suggestive of sepsis, making liver biopsy rarely necessary. Should a liver biopsy be obtained, a fairly benign periportal inflammatory infiltrate with bile duct plugging may be observed. Fortunately, cholestasis improves with antibiotic therapy and resolution of the infection, although improvement of LFTs may lag behind clinical improvement.

Drug Hepatotoxicity

Numerous medications may cause abnormal increases in the LFTs. In patients receiving methotrexate for GVHD prophylaxis, an elevated bilirubin is almost universal during the first 2 weeks. A list of commonly used drugs associated with elevations in the LFTs is given in Table 48-2, along with their hepatic side effects. There is a chapter on drug-induced liver disease (see Chapter 122, "Chronic Cholestasis and its Sequelae").

Iron Overload

Hemosiderosis is a common late problem that arises from the multiple blood transfusions as well as increased red blood cell turnover as a consequence of a hematologic malignancy. Iron deposition in the liver begins in the Kupffer cells, but may eventually extend to hepatocytes. Hemosiderosis has been associated with cardiomyopathy and liver injury, such that phlebotomy is generally recommended for those individuals with excessive iron stores as

TABLE 48-2. Commonly Used Drugs Associated with Abnormal Liver Function Tests and Clinical Liver Disease

Drug Cholestasis Hepatitis Liver Failure

Cyclosporine A Tacrolimus

Trimethoprim-sulfomethoxizole + + +

Piperacillin/Tobramycin + +

Fluconazole

Amphotericin B

Cotlrtimaxzole

Pentostatin

Mycophenolate mofetil Methotrexate +

determined by elevations of the serum ferritin and trans-ferrin saturation as well by an increased hepatic iron content on liver biopsy. LFTs may improve with phlebotomy. Chapter 125, "Hereditary Hemochromatosis" is devoted to hemochromatosis.

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