Hyperlipidemia is not unusual in liver transplant recipients, but refractory severe hyperlipidemia is unusual. We treated a 39-year-old man who had severe dyslipidemia after liver transplant. The levels of blood lipids, liver enzymes, and essential indicators of liver pathology were monitored. The first serum sample was collected from the liver recipient 56 days after transplant surgery because samples could not be obtained sooner after the transplant. The levels of liver enzymes and blood lipids were improved with symptomatic treatment but had recurrent fluctuations. Tacrolimus and cyclosporine, even at low doses, may have been the dominant factor affecting the blood lipid levels in the recipient.
Key words : Toxicity, Infection, Acute rejection
Hyperlipidemia is common in patients who have had liver or kidney transplant.1,2 The posttransplant incidence of dyslipidemia is 70% in liver recipients, markedly higher than before transplant. Hyperlipidemia is the major risk factor for cardiovascular diseases and death in transplant recipients.3 Although age, weight, and genetics may play a role, medications may be the predominant triggers of dyslipidemia in liver transplant recipients, especially calcineurin phosphatase inhibitors, rapamycin, and glucocorticoids.2 The incidence of fatty liver is higher in transplant recipients who have than do not have preexisting nonalcoholic fatty liver conditions.4-6 Literature search showed no prior report that correlated acute rejection or infection with hyperlipidemia. The degree of increase in cholesterol or triglycerides usually is limited in liver transplant recipients. We report a rare case of refractory dyslipidemia after liver transplant in a Chinese patient who sustained hyperlipidemia associated with acute rejection, infection, and high doses of medication.
The patient was a 39-year-old man with a 3-year history of liver enzyme fluctuation. He was diagnosed with alcoholic fatty liver disease-induced cirrhosis in 2011, and he did not have hepatitis C, autoimmune diseases, or hereditary liver disease. The hepatitis B virus (HBV) serum markers were positive including antibody to hepatitis surface antigen, antibody to hepatitis B e antigen, antibody to hepatitis B core antigen. The HBV DNA test was negative (< 100 IU/L), and no specific precautions were taken prior to the surgery for the prevention of hepatitis B recurrence. The liver pathologic diagnosis included alcoholic liver injury with severe fibrosis and neutrophil infiltration (Figure 1).
Orthotopic liver transplant was performed on September 25, 2012, and there were no complications after the surgery. The liver donor was a 33-year-old man who died in an automobile accident. The transplant recipient received tacrolimus, myco-phenolate mofetil, (MMF), and prednisolone acetate as antirejection treatment. The total cholesterol and triglyceride levels were normal before transplant. At 2 months after transplant, the levels of alanine aminotransferase (ALT), total bilirubin (TBIL), triglycerides, and total cholesterol began to fluctuate (Figure 2). Low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and apolipoprotein also fluctuated with the cholesterol and triglyceride levels. The LDL-C levels remained elevated and HDL-C levels were intermittently decreased. In February 2013, the HBV DNA level was 118 IU/mL, and the patient was treated with entecavir. Beginning on March 9, 2013, the patient received atorvastatin and intermittent fenofibrate for treatment of blood lipid levels. After transplant, the patient abstained from alcohol but he had many fluctuations in the levels of blood lipids and liver enzymes (Figure 2).
The test results on November 20, 2012, showed a tacrolimus blood level 22.9 ng/mL, and retesting on November 27, 2012 (66 d after transplant), showed tacrolimus blood level 29.10 ng/mL, TBIL 26 μmol/L, direct bilirubin 20.4 μmol/L, alkaline phosphatase (ALP) 174 U/L, γ-glutamyl transpeptidase (GGT) 120 U/L, total cholesterol 13.92 mmol/L, and triglycerides 36.75 mmol/L. The abdominal computed tomography (CT) scan showed severe hepatic adipose infiltration. Based on these results, tacrolimus was stopped immediately, and tacrolimus 1 mg every 12 hours was started on December 2, 2012. The levels of liver enzymes and blood lipids returned to normal, but similar incidences of elevated levels occurred in the subsequent 2 months regardless of the administration of tacrolimus or cyclosporine. The toxicity of the medications may have been the main triggering factor.
On March 9, 2013 (165 d after transplant), the test results showed abnormal levels of hepatic enzymes and blood lipids (ALT 211 U/L, aspartate aminotransferase [AST] 254 U/L, TBIL 52.1 μmol/L, ALP 92 U/L, GGT 138 U/L, total cholesterol 7.25 mmol/L, and triglycerides 20.51 mmol/L), and the tacrolimus blood level was 2.4 ng/mL. The liver pathology results showed acute rejection and moderate steatosis (Figure 3). The levels of liver enzymes and blood lipids were restored after high-dose methylprednisolone pulse therapy. On April 11, 2013, the patient was again diagnosed with acute rejection based on the pathology results, and methylprednisolone treatment was administered. The patient was treated with oral tacrolimus 1.5 mg every 12 h, MMF 750 mg every 12 h, ursodeoxycholic acid, entecavir, atorvastatin, and fenofibrate.
In late June 2013, the patient experienced poor appetite, nausea, and vomiting. The test results from July 5, 2013 (283 d after transplant) showed ALT 76 U/L, AST 250 U/L, TBIL 50 μmol/L, creatinine 511 μmol/L, total cholesterol 4.62 mmol/L, triglycerides 5.46 mmol/L, and tacrolimus level 18.5 ng/mL. The pathology results of liver biopsy showed severe steatosis and chronic drug-induced liver injury (Figure 3). Tacrolimus was discontinued, and the levels of creatinine, blood lipids, and liver enzymes decreased but remained above normal. Tacrolimus was reintroduced to the regimen but had negative effect on liver function. Therefore, in the subsequent treatment, MMF was used alone as the antirejection agent, and MMF dose was increased to 1 g every 12 h on August 6, 2013.
The test results on August 9, 2013 (318 d after transplant) showed ALT 104 U/L, AST 504 U/L, TBIL 54.9 μmol/L, total cholesterol 5.13 mmol/L, triglycerides 13.67 mmol/L, ALP 193 U/L, GGT 203 U/L, and tacrolimus level 4 ng/mL. The patient gradually developed ascites and fever. The test of leukocyte number in ascites indicated peritonitis, and levofloxacin hydrochloride was administered to treat the infection. The pathology results of liver biopsy on August 22, 2013, indicated that (1) the liver showed subacute septic change, equivalent to grade G3 (Metavir scoring system) because bacterial infection was the cause and there was liver cell necrosis present in some areas; and (2) the liver cells showed moderate steatosis, characterized by the presence of large and small vesicles and microvesicles (Figure 3). After treatment with piperacillin and tazobactam for 10 days, the fever was controlled, and the levels of liver enzymes and blood lipids were improved. On September 24, 2013, the patient had recurrent fever and elevated levels of liver enzymes and blood lipids, and treatment was repeated with piperacillin and tazobactam.
On October 3, 2013 (373 d after transplant), the levels of blood lipids were elevated (ALT 38 U/L, AST 90U/L, TBIL 20.3 μmol/L, total cholesterol 4.01 mmol/L, and triglycerides 12.34 mmol/L). The levels continually increased, and blood tests on October 15, 2013 showed ALT 44 U/L, AST 170 U/L, TB 39.8 μmol/L, ALP 265 U/L, GGT 634 U/L, triglycerides 14.25 mmol/L, total cholesterol 6.80 mmol/L, procalcitonin 0.894 ng/mL, and normal hemogram. The liver pathology showed acute rejection (Figure 3). Methylprednisolone was prescribed (8 mg/d) to control the rejection, and methylprednisolone dose was reduced to 4 mg on October 29, 2013. Cefoperazone and sulbactam were prescribed to treat the infection. The levels of liver enzymes and blood lipids were improved but continued to fluctuate. Methylprednisolone was discontinued on November 9, 2013, and basiliximab was introduced to control the immune responses. The levels of liver enzymes and blood lipids were reduced almost to normal. The test results on November 29, 2013, showed ALT 37 U/L, AST 53U/L, TB 29.2 μmol/L, ALP 118 U/L, triglycerides 0.99 mmol/L, and total cholesterol 2.91 mmol/L.
The clinical course of this case suggested that the abnormal levels of liver enzymes and blood lipids may have resulted from the drug toxicity of tacrolimus and cyclosporine. This was supported by the clinical features and pathologic evidence. Several previous studies indicated that hyperlipidemia is associated with the drug toxicity of tacrolimus and cyclosporine. Li and colleagues performed a follow-up study 6 months after transplant on 77 transplant patients and concluded that the incidence of hyperlipidemia was 29.9%.7 Higher levels of tacro-limus were associated with hyperlipidemia. All commonly used antirejection medications can affect blood lipid levels and may be an important factor in the high incidence of hyperlipidemia in posttransplant patients.8 Sirolimus is a strong trigger of hyper-lipidemia. It can act on the insulin pathway, particularly when combined with cyclosporine.9,10 Cyclosporine may affect the production of bile acid 26-hydroxylase inhibitor, thus slowing the synthesis of bile acids from cholesterol and transport of cholesterol to bile and the small intestine. In comparison, dyslipidemia induced by tacrolimus is rare and mild. Nonetheless, both medications may lead to hyperlipidemia.11,12
Hormones can cause insulin resistance and dyslipidemia. Currently, the medications commonly are used to treat blood lipid levels, especially 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (also known as statins). Pravastatin is the best studied and most commonly used statin for posttransplant patients because its metabolism does not require the cytochrome P450 enzyme system.13 Furthermore, pravastatin may have immuno-suppressive functions that can help decrease acute or chronic rejection responses in transplant recipients.14
In the present case, the dose of tacrolimus was adjusted frequently, but the tacrolimus concentration remained unstable. Even at lower doses, tacrolimus resulted in abnormal levels of blood lipids and liver enzymes. In contrast, long-term use of atorvastatin combined with intermittent use of fenofibrate did not improve blood lipid levels significantly. It was difficult to achieve a balance between acute rejection and drug toxicity; sometimes, these 2 processes were not readily distinguishable when the concentration of tacrolimus was low. The abnormal liver function during acute rejection may further slow drug metabolism. Therefore, drug toxicity may induce hyperlipidemia even at low drug concentration in blood. High-dose MMF and delayed tacrolimus treatment may suppress the immune responses in the liver transplant recipient, and occasionally tacrolimus may be unnecessary.15,16 Considering the toxicity of tacrolimus, we attempted to use MMF alone as the antirejection agent for 2 months, but eventually it was not effective. Currently, tacrolimus is not being used in this patient. The combination of MMF and basiliximab is being used to control rejection. Hyperlipidemia is temporarily under control, and the levels of liver enzymes are restored to normal with this combination. The long-term antirejection treatment regimen is yet to be evaluated.
In this case, tacrolimus was discontinued before the patient had infection, and drug toxicity was mild. The dyslipidemia was obviously mitigated when the infection was brought under control. In addition, the levels of blood lipids fluctuated with hepatic enzyme levels. It is plausible that the hyperlipidemia was affected mainly by liver function. A possible mechanism is that, in the presence of infection or rejection, the elevated levels of ALP and GGT supported that the liver may have had cholestatic injury which may have caused abnormal levels of blood lipids. Cheluvappa and coworkers considered that hyperlipidemia may be an important response to Gram-negative bacterial sepsis, and the mechanisms may include tissue lipoprotein lipase inhibition, up-regulated hepatic triglyceride production, and defenestration of the liver sinusoidal endothelial cells by bacterial toxins.17 There are few reports about infection-associated hyperlipidemia, but Chelu-vappa’s was supportive of our investigation. The patient in our case had dyslipidemia under a variety of circumstances. It was necessary to take into consideration any possible defects in his genetics, immune system, or metabolism. In addition, we observed many similarities in some clinical features before and after liver transplant such as fatty change of the liver, predisposition for autoimmune diseases prior to transplant, and liver pathology, particularly the fourth pathology test after transplant. Such similarities included the aggregation of neutrophils and fatty changes. All these features indicated that it was likely that the patient incurred the same conditions that he had prior to transplant. Alcoholic cirrhosis may not necessarily be among them because the diagnosis prior to transplant may not have been accurate. The patient’s blood lipid levels were mostly normal prior to transplant. He had no family history of hyperlipidemia, and his likelihood of genetic defects was rare. The levels of immunoglobulin, negativity of autoantibodies, and pathology results provided no evidence for the diagnosis of autoimmune liver disease. The mechanism of dyslipidemia in this patient should be further investigated. Currently, the fluctuations in the levels of hepatic enzymes and blood lipids have been treated effectively with antirejection treatment with tacrolimus. By using the combination of MMF and basiliximab, we might avoid the need for a second transplant in this patient.
Volume : 13
Issue : 4
Pages : 371 - 375
DOI : 10.6002/ect.2014.0051
From the 1Department of Transplantation, 302 Hospital, Beijing,
China and the 2Department of Orthopedics, 309 Hospital, Beijing,
Acknowledgements: The authors Zhou Xia and Luo Xiao-bo contributed equally to this work. The authors have no conflicts of interest to declare. No funding was received for this study.
Corresponding author: Zhang Min, Department of Transplantation, 302 Hospital, Beijing, China
Phone: +86 10 6693 3437
Fax: +86 10 6693 3437
Figure 1. Histologic Evaluation of the Recipient Liver Tissue Before Liver Transplant
Figure 2. Fluctuation in the Levels of Alkaline Phosphatase (ALT), Total Bilirubin (TBIL), Total Cholesterol (TC), and Triglycerides (TG) After Liver Transplant, Indicating Dyslipidemia in the Recipient
Figure 3. Histologic Evaluation of the Liver Tissue After Liver Transplant