© Springer Science+Business Media New York 2016
Paul J. Thuluvath (ed.)Disease Recurrence After Liver Transplantation10.1007/978-1-4939-2947-4_99. Recurrence of Metabolic Disorders After Liver Transplantation
(1)
Department of Hepato-Pancreato-Biliary/Liver Transplantation Surgery, Cleveland Clinic, 9500 Euclid Avenue, Desk A-100, Cleveland, OH, USA
(2)
Transplant Center, Cleveland Clinic, Cleveland, OH, USA
Keywords
Liver transplantationMetabolic liver diseaseDisease recurrence9.1 Introduction
The liver is often either affected by metabolic disorders or is the cause of certain metabolic diseases. Liver transplantation has proven to be effective in correction of these disorders. Most, if not all these diseases are cured with LT when medical and supportive measures fail to correct the problem or abnormalities as the result of these disorders. However, depending the timing of LT, certain consequences of these problems may persist in the long round. These disorders could be as a result of inherited disorders of copper and iron metabolism (Wilson’s Disease and hemochromatosis), storage of abnormal production of certain proteins (amyloidosis), abnormalities in metabolic pathways of production or elimination of certain proteins (hepatic porphyria, primary hyperoxaluria), or other inherited genetic disorders (familial hypercholesterolemia).
In this chapter, we will briefly discuss about these disorders and outcomes of LT and will focus on possible recurrence of these diseases and effects of LT on the disease process.
9.2 Familial Amyloidosis
Transthyretin (TTR) is a soluble transport protein for thyroxin and vitamin A. The protein is mainly synthesized by the liver. Amyloid fibril formation and deposition is the product of mutation in only one allele. TTR amyloidosis is a hereditary autosomal dominant disease and more than 100 mutations associated with the disease have been described [1, 2]. Familial amyloid polyneuropathy (FAP) manifests itself in adult life and usually after the fourth decade of life [1], with variable disease pattern based on the TTR mutation. The neuropathy caused by the disease is induced by deposits of fibril protein alongside the nerves leading to loss of pain and temperature sensation in the feet with long-term impairment of walking, and autonomic dysfunction leading to cardiac conduction defects, and gastrointestinal and bladder motility disorders, leading to death in 10–15 years [2]. The clinical manifestations of the disease vary according the type of mutation. The most common mutation worldwide is TTR V30M, which is mostly seen in Portugal, Sweden, and Japan. The abnormal protein is made in the liver, and this is the basis for LT in this disease to stop the formation of the abnormal protein. Because of the short half-life of TTR in the blood, the concentration of abnormal protein should decrease to undetectable levels in few days.
The first LT for TTR amyloidosis was done in 1990 [3]. In 1993 with more encouraging outcomes, LT became acceptable treatment for FAP [4]. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry , over 2060 patients with TTR amyloidosis have been transplanted [5]. The estimated 10-year survival probability of LT for common variant amyloid is about 100 % compared to 56 % for non-transplant patients [6]. Result of 5-year survival for LT in non-V30M patients is far inferior (59 %) [7].
Effect of LT on improvement of pre-transplant neurological manifestation is guarded. Despite disappearance of abnormal protein from circulation, the old deposits are there to stay with less chance of recovery. Regression of amyloid deposits in the peripheral nerves is uncertain [8]. There is contradictory histological evidence in favor of persistence of autonomic neuropathy after LT [9]. There are several reports of progression of cardiomyopathy after LT for FAP, predominantly for non-V30M patient [10], with more progression in older age group [11].
There are several factors to consider for more successful liver transplantation: (1) Age less than 50; (2) Duration of symptoms less than 7 years; (3) Low level of polyneuropathy; (4) Low BMI; (5) No severe autonomic dysfunction; (6) Absence of amyloid cardiomyopathy; (7) No significant renal dysfunction [12, 13].
Multiple organ transplantation is common in patients with severe amyloid cardiomyopathy (liver–heart) and renal insufficiency (liver–kidney). According to the report from FAPWTR, there have been 46 combined heart–liver transplants and 47 combined kidney–liver transplants in FAP patients [5]. Most of the combined heart–liver transplants were performed in non-V30M cases. This is indicative of higher and earlier predisposition of cardiomyopathy in these patients [14, 15].
Liver transplantation is a curative procedure to stop formation of abnormal protein in TTR-FAP; however, the preexisting problems and symptoms may remain unchanged or even continue to progress. The patient selection for LT in FAP is extremely important to have good outcomes. The potential risk factors for poor outcome should be considered when evaluating a patient to be placed on the waiting list for LT. With novel medical therapies directed at prevention of protein deposits or mobilization of the already-deposited fibrils, there is a hope to have better results in prevention of progression of the disease early on after diagnosis, or prevention of deterioration of neurological manifestation when combined with LT in these patients.
9.3 Hemochromatosis
Hemochromatosis is a state of pathological iron overload which is due to a genetic disorder that results in excessive intestinal iron absorption. The nature of symptoms is nonspecific making it difficult to diagnose the disease. It was not until 1996 where the discovery of the hemochromatosis gene (HFE) brought new insights about the disease and learning of its natural history and making strategies to diagnose the disease [16, 17]. The most common form of hereditary hemochromatosis is due to mutation C282Y and its homozygosity [18]. The discovery of hepcidin and ferroprotein and their regulatory function in release of iron from enterocytes and monocytes to plasma were the essential steps in learning about the disease process and role of the liver transplantation in the treatment of the disease. The liver is the major site of hepcidin synthesis and at the same time site of excess iron storage. This makes the organ essential in maintaining normal systemic iron homeostasis. In patients with HFE-hemochromatosis, production of hepcidin is down regulated and as a result iron homeostasis is disturbed leading to increased absorption of iron from the intestine and accumulation of it in the hepatocytes leading to the development of hepatocyte damage and eventually to end-stage liver disease. Liver transplantation has shown to lead in normal hepcidin production and its plasma levels and this leads to iron homeostasis and prevention of excess accumulation of iron in the transplanted liver [17].
The initial report on LT for hemochromatosis was from Pittsburgh on six patients. Based on this report, all the patients were alive 6 months after transplantation [19]. Following this report, several uncontrolled studies suggested that patients with iron overload have poor outcome after LT and mostly die of infection and cardiac issues [20–22]. This was further proven in the first multicenter study based on the report from national hemochromatosis transplant registry [21]. However, another study based on information from United Network for Organ Sharing from 1990 to 2006, Yu and Ioannou looked at two periods of transplantation between 1990–1996 (177 patients) and 1997–2006 (217 patients). One-, 3-, and 5-year survival in the first period was 79.1 %, 71.8 %, and 64.6 %, respectively, compared to national average post-LT recipient survival of 86.4, 79.5, and 73.8 % with hazard ratio of 1.38 for those who were transplanted for hemochromatosis. In contrast, in the second period patients with hemochromatosis had excellent survival and comparable with the national post-LT survivals of 88.4 %, 80.3 %, and 77.3 %, respectively, for 1-, 3-, and 5-year survival with hazard ratio for death of 0.89. They attributed the low survival in the first period to high number of patients with hepatocellular carcinoma. In this survey, patients with hemochromatosis were more likely to die of cardiovascular disease than other cause of graft failure and infection [23].
Excess iron deposit in other organs like heart and pancreas is a major cause of morbidity in patients with hemochromatosis and iron overload leading to diabetes and cardiac dysfunction. Cardiac involvement in iron overload may lead to cardiac failure and is a major cause of post-LT morbidity and mortality. In patients with major cardiac involvement, successful combined heart and liver transplantation has been reported [24].
In general, LT is a cure for patients with hemochromatosis and iron overload. Consequences of longstanding excess iron in other organ systems could potentially affect the long-term outcomes. In patients with secondary hemochromatosis, unless the primary disorder is treated, there is a chance for eventual re-accumulation of iron.
9.3.1 Wilson Disease
Wilson’s disease is an inherited autosomal-recessive disorder of copper metabolism. The disease is characterized by excessive deposition of copper in the body with predominant involvement of the liver, brain, kidneys, and corneas. The disease mostly presents itself with neurological manifestations in adolescents and young adults with signs of progressive hepatic dysfunction. Remarkable improvements have been achieved with medical therapy with chelating agents in patients with resolution of symptoms, even in more advanced cases of the disease. In situations where medical therapy has failed or in new cases presenting with acute liver failure, liver transplantation has proven to be the accepted treatment. Improvement of neurological manifestations of the disease in the form of dementia, psychosis, extrapyramidal or cerebellar signs after liver transplantation has been a matter of controversy in reported series. In a report from the University of Pittsburgh on 45 patients with an age range of 8–52 years, 30 patients were transplanted for acute or subacute liver failure and the remaining 15 for chronic liver disease. One-, 5-, and 10-year patient survival was 73.3, 73.3, and 68.9 %. Of these patients, 17 had neurological manifestations at the time of transplant. Twelve of these patients survived showing improvement in nine patients [25]. In another multicenter study from France on 121 patients (adults and pediatrics), 89 % of patients survived at 1 year and 87 % at 5, 10, 15, and 20 years. Out of 19 patients with neurological manifestations at transplant, follow-up data were available for 11 patients. Of these 11 patients, 8 patients experienced partial or complete neurological improvement and three remained with stable condition [26].
The US transplant registry of 170 pediatric patients and 400 adults with Wilson’s disease showed excellent outcomes after liver transplantation. The overall 1- and 5-year survival was 90.1 and 89 % for children and 88 and 86 % for adults [27].
Liver transplantation is a cure for patients with Wilson disease who failed medial therapy or in those with late initial presentation with complications of the disease, including acute liver failure with excellent long-term outcomes. Over 50 % improvement has been reported in those transplanted with neurological manifestation of the disease.
9.4 Homozygous Familial Hypercholesterolemia
Familial hypercholesterolemia is an autosomal dominant inherited disease and is associated with severe atherosclerosis and early death secondary to cardiovascular complications. The disease is mostly due to a mutation in low density lipoprotein (LDL) receptor gene. The heterozygous form of the disease develops later in life and usually around fourth and fifth decade with an incidence of 1:500. These patients have lower cholesterol levels than homozygotes. The homozygous form occurs rarely, 1:1,000,000, and develops in childhood. Most of the involved patients die before the age of 20 secondary to severe atherosclerosis and cardiovascular complications [28–30].
Medical therapy for these patients consists on low-fat diet with high doses of lipid-lowering agents, though there is low response rate to these medications. Weekly LDL apheresis to lower the cholesterol level is the integral part of therapy in prevention of accelerated atherosclerosis [31–33].
Liver transplantation is the only effective treatment in patients with homozygous familial hypercholesterolemia. The timing of transplant in these patients is a matter of controversy. It is preferable to do LT in childhood before the appearance of cardiovascular complications, however, a preemptive LT has not been considered as the treatment of choice because of the short- and long-term complications including rejection and side effects of immunosuppressive drugs such as renal insufficiency. Patients who received a liver from their living heterozygous parents showed slight reduction of LDL-cholesterol and continued to require life-long lipid-lowering agents after LT [34, 35]. In patients with extensive cardiac disease, combined transplantation of liver and heart is the treatment of choice with excellent survival [36–38].
Liver transplantation for homozygous familial hypercholesterolemia is the only cure for the disease. Emerging therapies such as novel therapeutic agents and LDL apheresis are useful in prevention of development of cardiovascular complications and to delay the need for LT.
9.4.1 Primary Hyperoxaluria Type 1
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive liver disease caused by a deficiency of the enzyme alanine glycoxylate aminotransferase (AGT) found within hepatic peroxisomes [39–41]. It can occur at any age—from birth up to the sixth decade of life with the median age of onset of 5.5 years [42]. This enzyme is involved in the final step of glyoxylate metabolism and its deficiency leads to increased synthesis and excretion of oxalic acid which causes renal oxalate stones, oxalosis of the kidney, and eventually to end-stage renal disease. Renal replacement therapy and other supportive measures cannot take care of this excess oxalate and as a result oxalate crystals are deposited in many different organs, leading to musculoskeletal, joint, cardiovascular, and peripheral nervous system complications.
The initial trials with kidney transplantation (KT) alone were not successful, other than rare occasions, because of continuous overproduction of oxalate due to defective metabolic pathway in the native liver and re-accumulation of oxalate in the transplanted kidney [43].
Since the liver is the organ responsible for this metabolic disorder, isolated preemptive LT might be considered as the treatment of choice in patients with the disease and before complete failure of their renal function and when the Glomerular filtration rate (GFR) is approaching 40 mL/min/1.73 m2. Because of the heterogeneity of the disease and advances in conservative management of these patients and also risks involved with LT procedure and outcomes, preemptive LT brings up medical and ethical questions [44].
Dual liver and kidney transplant (LKT) is the treatment of choice for patients with PH1 and end-stage kidney disease when GFR is less than 15 mL/min. Deterioration of renal function to this level results in decrease in clearance and increase in retention of oxalate. These patients should be placed on vigorous hemodialysis and planned combined LKT. Outcomes of solitary KT and combined LKT in patients with hyperoxaluria from the US registry indicates 5-year survival rate of 45 and 14 % for KT alone in adults and pediatric patients and 64 and 76 % for LKT in these patients. Low rate of survival in pediatric patients after KT alone could be a reflection of more severe disease with early onset of the disease [43, 45, 46].
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