Objectives: This study sought to evaluate the efficacy of liver transplant for unusual liver diseases.
Materials and Methods: The results of 476 patients who underwent liver transplant from 1988 to January 2015 were retrospectively analyzed. Two hundred forty-five of them were adult patients and 231 of them were pediatric. Thirty-one patients had unusual liver disease.
Results: Of the 31 patients with unusual liver disease, 9 (29%) were adult and 22 (71%) were pediatric patients. In the pediatric group, indications for liver transplant were Alagille syndrome (n = 5), Crigler-Najjar syndrome type 1 (n = 5), glycogen storage disease (n = 3), oxalosis (n = 3), familial hypercholesterolemia (n = 2), alpha-1-antitrypsin deficiency (n = 2), Caroli disease (n = 1), and cystic neuroblastoma metastasis (n = 1). Six patients (27.2%) had acute rejection episodes and were successfully treated with pulse steroids. In 2 patients, retransplant was performed for chronic rejection. Three patients died during follow-up (13.6%): 2 because of sepsis and 1 because of cranial hemorrhage. In the adult group, indications for liver transplant were neuroendocrine tumor metastasis (n = 1), liver angiosarcoma (n = 1), familial hypercholesterolemia (n = 2), alveolar hydatid disease (n = 2), cystic fibrosis (n = 1), congenital hepatic fibrosis (n = 1), and oxalosis (n = 1). Four patients (44.4%) had acute rejection episodes and were successfully treated with pulse steroid therapy. One patient died due to the recurrence of primary disease (liver angiosarcoma) during follow-up (11.1%).
Conclusions: Advances in liver transplant and our understanding about unusual liver disease have led to significant improvements in managing these diseases. Liver transplant effectively treats the underlying defect and the complications of portal hypertension, or risk of malignancy for those disorders, in which the liver is affected.
Key words : Alagille syndrome, Alveolar hydatid disease, Crigler-Najjar syndrome type 1, Familial hypercholesterolemia
The only potentially lifesaving intervention for acute liver failure or end-stage liver disease is liver transplant. All over the world, the common indications for liver transplant include hepatitis B, hepatitis C, alcoholic cirrhosis, and hepatocellular carcinoma. However, some more unusual liver diseases, such as liver-based metabolic abnormalities and tumor metastasis, can be treated with liver transplant.1-3 The aim of this study was to evaluate the efficacy of liver transplant for unusual liver diseases.
Materials and Methods
We retrospectively analyzed the results of 496 patients who underwent liver transplant from 1988 to August 2015 at our liver transplant center in Turkey (255 adult and 241 pediatric patients). Thirty-one of these patients had unusual liver disease. In all patients, we recorded sex, age, cause, donor type, complication, acute rejection episodes, and mortality. This study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all participants.
All biliary and vascular anastomoses were performed with loupe magnification (original magnification × 2.5). All patients received tacrolimus-based immunosuppression. Tacrolimus blood levels were maintained between 10 and 15 ng/mL during the first month and subsequently between 5 and 10 ng/mL. Methylprednisolone (10 mg/kg) was administered intraoperatively and was continued postoperatively from 10 mg/kg, tapered to 0.1 mg/kg at the end of the first month, and stopped at the end of the third month. Patients received prophylaxis against fungi, viruses, and Pneumocystis for 6 months after surgery.
Ultrasonographic examination of hepatic perfusion was performed twice daily during the first week after transplant. In addition, routine ultrasonographic examinations were scheduled 1 month after orthotopic liver transplant and at 3-month intervals thereafter. A heparin drip infusion was begun on the day of transplant and was adjusted to maintain active coagulation time (whole blood) trough levels between 150 and 200 seconds. Heparin infusion was continued for 1 week; after that, anticoagulation therapy consisted of aspirin (40 mg daily) and dipyridamole (4 mg/kg 3 times daily). No protocol liver biopsy specimens were obtained, and biopsies were performed only for investigation of biochemical abnormalities (elevated serum transaminase or bilirubin levels). There was no donor mortality or major morbidity.
Of the 31 patients with unusual liver diseases treated with liver transplant, 9 were adult patients (29%) and 22 were pediatric patients (71%). In the pediatric group, indications for liver transplant were Alagille syndrome (n = 5), Crigler-Najjar syndrome type 1 (n = 5), glycogen storage disease (n = 3), oxalosis (n = 3), familial hypercholesterolemia (n = 2), alpha-1 antitrypsin deficiency (n = 2), Caroli disease (n = 1), and cystic neuroblastoma metastasis (n = 1) (Table 1). Eleven patients (50%) were female. The mean age of the patients was 6.8 years (range, 2 mo-16 y). Nineteen were living-donor liver transplant and 3 of them were deceased-donor liver transplant recipients. In this group, none of the patients had any vascular complications. In 7 patients (31.8%), biliary leakage occurred. Three did not require treatment, and 4 were treated with interventional radiologic procedures. Six patients (27.2%) had acute rejection episodes and were treated with pulse steroid therapy. In 2 patients, retransplant was performed because of chronic rejection. Three patients died during the follow-up (13.6%), 2 because of sepsis and 1 because of intracranial hemorrhage. The details of the patients are shown in Table 1.
In the adult group, indications for liver transplant were neuroendocrine tumor metastasis (n = 1), liver angiosarcoma (n = 1), familial hypercholesterolemia (n = 2), alveolar hydatid disease (n = 2), cystic fibrosis (n = 1), congenital hepatic fibrosis (n = 1), and oxalosis (n = 1) (Table 2). Seven were living-donor liver transplant and 2 were deceased-donor liver transplant recipients. Four patients (44.4%) had acute rejection episodes and were successfully treated with pulse steroid therapy. In the adult group, there were no vascular complications. At the early period after surgery, 3 patients (33.3%) displayed biliary leakage. All were treated with interventional radiologic procedures. One patient (11.1%) died because of recurrence of primary disease (liver angiosarcoma) during follow-up.
Caroli disease is a congenital disorder that causes liver failure. It is a rare disorder, with a prevalence of 1 in 1 million people.4 The pathology starts in the intrauterine period,5 and it is characterized by multifocal fibrocystic dilatation of the intrahepatic bile ducts.4-6 Caroli disease can be seen at any age,4 but it is more common in those in their twenties.7 Most of the patients present to the hospital with abdominal pain, fever, hyperbilirubinemia, elevated alkaline phosphatase, hepatomegaly, or symptoms of portal hypertension.4,7 Caroli disease is characterized by recurrent episodes of biliary obstruction, cholangitis, hepatolithiasis, and liver abscesses. There are 2 treatment options for Caroli disease. Up to 87% of patients can be treated with liver resection.4 To decide between liver transplant or resection, liver functions, portal hypertension, hepatic fibrosis, extent of the disease, and suspect for cholangiocarcinoma must be evaluated. If there are signs of liver failure, liver transplant is recommended.4,7 In the literature, most patients who are treated with liver transplant for Caroli disease are adult patients,8 and graft and patient survival rates are no different from those shown in patients who undergo orthotopic liver transplant for other causes of chronic liver disease.7,8 Our patient was an 8-year-old female patient. She had good graft survival with no complications and no rejection episodes.
Alagille syndrome is a genetic disease in which patients share the characteristic features of a paucity of interlobular bile ducts and chronic cholestasis, accompanied by various combinations of cardiovascular malformations and cutaneous manifestations, including jaundice, itching, and widespread xanthomatosis.9 Liver transplant is the treatment of choice for children with the severe hepatic form of Alagille syndrome.10 Without liver transplant, a patient with this highly debilitating disease has just a 50% chance of reaching 19 years of age; however, the likelihood of long-term survival after transplant is 87%.11 We published results for our first patient in 2001.10 At transplant, this patient was 15 years old. Two years after transplant, retransplant was performed because of chronic rejection. In the present series, 1 patient died because of sepsis after transplant. The other 4 patient are still alive, and their grafts are still functioning.
Crigler-Najjar syndrome type 1 is a rare autosomal recessive disease. The disease is characterized by unconjugated hyperbilirubinemia. The main complication is deficiency of hepatic bilirubin uridine-diphosphate enzyme. In these patients, hyperbilirubinemia will cause neurotoxicity.12 Liver transplant is currently the only definitive treatment for Crigler-Najjar syndrome type 1, acting as a type of enzyme replacement therapy. Hyperbilirubinemia can be controlled by phototherapy until transplant. If phototherapy is not applied, kernicterus will occur, causing irreversible neurologic damage or death.12,13 Our first publication on this in 2009 included a 2-month-old infant, the youngest patient with Crigler-Najjar syndrome type 1 reported in the literature.14 In this series, mortality rate was 20% (n = 1). The other 4 patients are still alive with good graft function. These findings suggest that orthotopic liver transplant is curative for Crigler-Najjar syndrome type 1, with an excellent survival rate.
Familial hypercholesterolemia is a rare inherited condition with an incidence of 1 in 1 million.15 The major complication of familial hypercholesterolemia is that hypercholesterolemia leads to premature atherosclerosis, with early death from cardiovascular complications (eg, aortic valve disease, coronary artery disease). The other manifestation of familial hypercholesterolemia is cutaneous xanthomas, which is especially found on the elbows, hands, knees, and Achilles tendon. In this disease, blood lipid levels cannot be reduced by drugs. In the literature, the most effective treatment for reducing blood lipids was reported as lipid apheresis; however, this is an expensive treatment method and must be applied every 1 or 2 weeks. On the other hand, lipid apheresis cannot prevent systemic complications.16 The definitive treatment of familial hypercholesterolemia is liver transplant.15-17 In our institution, orthotopic liver transplants were performed in 4 patients (aged 11, 12, 19, and 19 y) for familial hypercholesterolemia. Before orthotopic liver transplant, aortic valve replacement was performed in 2 patients and coronary artery stenting was performed in 1 patient. After orthotopic liver transplant, cardiac complications were not seen in these patients. All patients’ lipid levels were normal, and they all had good graft function.
Cystic fibrosis is an autosomal recessive multisystem disorder in which defective epithelial chloride transports across membranes, causing dehydrated, thick, viscous secretions.18,19 Although pulmonary disease remains the main cause of morbidity and mortality, improved survival in patients with cystic fibrosis has led to an increased incidence of extrapulmonary complications, such as cirrhosis and pancreatic insufficiency.20 Liver failure and complications of portal hypertension are the common indications for liver transplant in cystic fibrosis patients.18 Our patient was 19 years old and had pulmonary disease and liver failure because of cystic fibrosis. He did not have pancreatic insufficiency. After transplant, uncontrolled pleural effusion occurred and pleurodesis was performed. During follow-up, he had no clinical problems. The patient is alive with good graft function Cystic neuroblastoma metastasis is the most common extracranial solid tumor in childhood and the most commonly diagnosed neoplasm during infancy that can metastasize to the bone, the bone marrow, the spleen, and the liver. The tumor can develop anywhere in the sympathetic nervous system including the adrenal glands. It may be solid (56%) or cystic (44%).21 In our patient with this disease, young age, multiple tumor-cell thrombi in the uninvolved liver sections, and positive peritoneal fluid cytology led us to treat her as stage 4 neuroblastoma.22 After undergoing a liver transplant, the patient underwent chemotherapy. During follow-up, she had no recurrence. The patient is alive with good graft function, with no reoccurrence.
Alveolar echinococcosis is a zoonotic disease mainly involving the liver with tumorlike lesions. The disease can infiltrate neighboring organs and can do hematogenous spread to distant organs such as the lung, the spleen, and the brain.23 When liver failure or complications such as chronic cholestasis Primary hyperoxaluria type 1 is a rare autosomal recessive disorder caused by the functional defect of the liver-specific peroxisomal, pyridoxal phosphate-dependent enzyme alanine, with glyoxylate aminotransferase leading to oxalate overproduction.24 Increased synthesis and subsequent and portal hypertension are uncontrollable with other treatments, transplant is the only treatment approach. In our patients with this disease, graft and patient survival rates were 100%.urinary excretion of the metabolic end-product oxalate result in insoluble calcium oxalate in the kidney and urinary tract.25 This situation usually results in renal failure. End-stage renal disease occurs in 50% of primary hyperoxaluria type 1 patients by 15 years of age and in 80% of patients by 30 years of age.24 The recommendation for oxalosis treatment is to do so before development of renal failure or liver-kidney combined transplant and after the development of renal failure. In our cases, 3 of the patients were under 18 years old and 1 was an adult patient (age 22 y). Three of the patients had kidney failure and were treated with hemodialysis. The other patient's glomerular filtration rate level was over 60%, and only liver transplant was performed. Another patient had combined liver-kidney transplant; however, this patient died because of intracranial hemorrhage before the transplant.
Glycogen storage disease, neuroendocrine tumor metastasis, congenital hepatic fibrosis, and liver angiosarcoma are the other rare conditions for liver transplant. In the literature, the mortality, morbidity, and graft survival rates are similar to other indications for liver transplant. For neuroendocrine tumor metastasis and liver angiosarcoma, the recurrence of primary disease is a major cause of mortality. In the present series, the patient who had a liver transplant for liver angiosarcoma died because of tumor recurrence.
In conclusion, liver transplant appears to be a feasible option and is associated with a better quality of life for patients with unusual liver diseases. In noncirrhotic liver diseases, liver transplant treats the defective functions and prevents the risk of malignancy. Selection of patients, timing of transplant, and pre- and postoperative care of patients are important for morbidity and mortality. Their outcomes are similar to the common causes of end-stage liver disease.
Volume : 15
Issue : 1
Pages : 128 - 132
DOI : 10.6002/ect.mesot2016.P11
From the Departments of 1General Surgery, the 2Department of Pediatric
Gastroenterology, and the 3Department of Anesthesiology, Baskent University,
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Prof. Mehmet Haberal, MD, FACS (Hon), FICS (Hon), FASA (Hon), Department of General Surgery, Baskent University, Ankara, Turkey
Phone: +90 312 212 7393
Table 1. Data of Pediatric Patients
Table 2. Data of Adult Patients