Unusual Indications for Transplantation

Primary Hyperoxaluria

Type 1 primary hyperoxaluria (PH1) is a rare autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine glyoxylate aminotransferase. As a result of this deficiency, overproduction of oxalate from glycine occurs in the liver and leads to progressive calcium oxalate formation, nephrocalcinosis, and eventually renal failure. Isolated kidney transplantation in patients with PH1 has failed universally because it does not cure the metabolic defect and has been associated with a high rate of graft loss because of disease recurrence. Although the liver is histologically and biochemically normal in primary hyperoxaluria, the enzymatic defect within the liver results in systemic hyperoxalosis. Liver transplantation corrects the metabolic defect of PH1 and will also reverse growth retardation related to PH1. To prevent recurrent renal failure in cases of PH1, combined simultaneous or sequential liver transplantation followed by kidney transplantation is performed.

There is as yet no standard approach to transplantation of patients with PH1. Most would agree that a patient with end-stage renal disease (ESRD) due to oxalate nephropathy secondary to PH1, who shows no response to pyridoxine, with no potential living donor for kidney transplantation, should receive a combined kidney and liver transplantation. Hyperdialysis and medical therapy should be used in these patients to reduce serum oxalate levels before and after combined kidney and liver transplantation. Ideally these measures should be initiated before kidney and liver transplantation. It is critical to minimize the time between the onset of ESRD and transplantation. After the combined liver-kidney transplant, there is a prompt fall in plasma oxalate concentrations. Nonetheless, urine oxalate levels remain markedly elevated for many months or even years after successful liver transplantation. The time required for resolution of hyperoxaluria following liver transplantation varies widely, occurring most rapidly in those who undergo transplantation within 6 months after reaching ESRD and who have undergone intensive dialysis. The use of isolated liver transplant as a bridge to later kidney transplant (sequential transplantation) has been fraught with problems, because the liver transplant recipient with continued renal failure and oxalosis is a special challenge.

Preemptive isolated liver transplant as an intentional strategy remains an option with good results for patients with chronic kidney disease stage 3 with a continuous decrease of glomerular filtration rate, in spite of aggressive medical therapy. Therefore there is only a narrow window in which isolated liver transplant may performed.

Domino liver transplant, in which a liver from a patient with oxalosis is transplanted into another individual with hepatic disease, has been done. However, outcomes have not been very successful. Results in a case report from Europe on five patients were dismal. Within the first 4 weeks, all the domino recipients developed dialysis-dependent kidney failure despite good liver function. Four of the five patients died. Other reports have shown similar results. Domino liver transplant using donors with PH1 results in early renal failure and cannot be recommended for transplantation unless preventive strategies have been identified.

Familial Homozygous Hypercholesterolemia

Familial homozygous hypercholesterolemia (FHH) is an autosomal recessive disease characterized by hypercholesterolemia and accelerated atherosclerosis leading to severe coronary artery disease. In severe cases (less than 2% of normal low-density lipoprotein [LDL] receptor activity), cardiovascular death is likely to occur within the first decade of life. These abnormalities are due to an intrinsic hepatocyte defect, specifically a reduction in LDL cholesterol (LDL-c) hepatocyte receptors with extraordinary elevation in serum LDL-c level. In patients with a less severe deficiency of the LDL receptor (2% to 30% of normal activity), the disease is likely to produce cardiovascular death within the second or third decade of life.

In the past, end-to-side portocaval shunting and ileal bypass were used to treat this condition in an effort to delay liver transplantation. Both these procedures have been discarded and replaced with the use of statin drugs and inhibitors of cholesterol absorption, as well as mechanical removal of plasma LDL by means of apheresis. Aggressive use of these drugs and LDL-apheresis may delay the development of atherosclerosis and overt cardiac disease in patients with FHH. Trials demonstrate that drugs that interfere with apolipoprotein B-100 metabolism (mipomersen and lomitapide) can further lower LDL-c by 25% to 55% in adult patients with FHH, but with hepatic and gastrointestinal side effects. Long-term studies to assess the safety and efficacy of these medications are needed in patients with FHH.

Because 75% of the LDL receptors are in the liver, liver transplantation becomes the treatment of choice for FHH for patients not responding to routine pharmacological treatments. Liver transplantation provides a source of normal LDL receptors that may clear cholesterol from plasma very effectively. Liver transplantation, before the onset of cardiovascular disease, offers the best chance for cure for patients with FHH, but it is not yet regarded as the treatment of choice and is generally considered only after the development of cardiovascular disease because of short- and long-term complications. Preemptive liver transplantation has been done with normalization of LDL-c levels and resolution of skin lesions 2 years after transplantation.

Living donor liver transplant from a parent is not an option because the parent is invariably a carrier of one copy of the defective gene(s). Patients with coronary artery disease are considered a high-risk group for liver transplantation. Coronary artery disease should be addressed before liver transplantation by percutaneous transluminal coronary angioplasty or coronary artery bypass grafting.

The current approach to FHH with severe cardiovascular disease is to perform either simultaneous or sequential heart-liver transplantation. Simultaneous transplantation is preferred if the heart graft functions immediately. In cases in which such is not the case, sequential transplantation can be accomplished. In both situations the heart relieves the cardiac disease (usually advanced coronary artery disease with ischemic cardiomyopathy), whereas the liver graft removes the underlying defect, a hepatic deficiency of LDL receptors. In most cases after liver transplantation, the serum cholesterol level declines markedly and in some cases can actually normalize. In patients who continue to have moderate degrees of hypercholesterolemia, statin drugs can be used to normalize the serum cholesterol level. There are two published cases of domino liver transplantation using a liver from a patient with FHH. Recipients developed hypercholesterolemia after liver transplant, but it was able to be controlled with diet and medication.

Familial Amyloid Polyneuropathy

Familial amyloid polyneuropathy is a dominantly inherited neuropathic form of amyloidosis caused by the hepatic production of a mutant transthyretin (TTR). Because TTR is produced almost exclusively by the liver, liver transplantation eliminates the underlying cause of the disease: production of an insoluble β-pleated mutant TTR that accumulates in peripheral and autonomic nerves. The disease is fatal with an expected survival of 12 to 15 years after the onset of clinical disease. The initial symptom is usually a peripheral neuropathy, although autonomic neuropathy with gastrointestinal and cardiovascular symptoms is also common. The presence of clinical autonomic neuropathy has a negative impact on both morbidity and mortality before and after liver transplantation.

Initially liver transplantation was performed in patients who were severely malnourished and those who had advanced peripheral or autonomic neuropathy. Because the disease resolves very slowly, if at all, as the deposited amyloid material is resolubilized and removed, these patients continue to experience their disease manifestations after transplantation. Thus the results are poor, and some recipients actually die of posttransplant malnutrition, sepsis (usually urosepsis), or cardiac arrhythmias as a consequence of their persistent amyloid-induced disease processes.

The current approach to patients with is to perform transplantation early after the initial onset of clinical manifestations of familial amyloid polyneuropathy their disease. Because the liver of these patients is normal except for its production of a mutant TTR protein, the liver explant in such cases is often used as part of a domino transplant despite the fact that the recipient of the explant domino liver will, with sufficient time, acquire the disease process (amyloid polyneuropathy). The period before the onset of clinical disease is usually long, between 10 and 50 years depending on variations in phenotypic expression of amyloid polyneuropathy in different endemic areas, so acceptance of a liver from a donor with familial amyloid polyneuropathy can be expected to provide the recipient of the domino liver with 10- to 50-year disease-free (polyneuropathy) posttransplant survival. For most transplant recipients in their mid-40s or 50s, this extra risk represents a minimal addition to the inherent risks of liver transplantation. In light of the current treatment and its outcome, several therapeutic research projects will become the clinical tool for slowing down the progress of familial amyloid polyneuropathy, including reduction of variant TTR levels in plasma downregulating TTR gene mRNA, inhibition of amyloid deposition, stabilization of the tetrameric TTR structure, and replacement of the variant TTR gene with the normal TTR gene (which can be achieved by liver transplantation or by gene therapy).

Protoporphyria

The erythropoietic porphyrias include two disorders characterized by excess production of free protoporphyrin from the bone marrow, due to either deficiency of the enzyme ferrochelatase (erythropoietic protoporphyria) or a gain-of-function mutation in the enzyme erythroid aminolevulinic acid synthase (X-linked dominant protoporphyria). The latter is less common but appears to carry a higher risk for liver disease.

Classically the disease is described as an autosomal dominant trait with incomplete penetrance. However, most patients have severely reduced ferrochelatase levels, thus suggesting the presence of two rather than one abnormal gene. Cases have been described in which both parents of an affected patient have a different gene defect with little or no clinical disease, but the combination of both abnormal genes in their offspring results in the phenotypic expression of overt protoporphyria. Regardless of the specific method of inheritance, affected patients have a unique form of immediate hypersensitivity to sun exposure characterized by a burning or stinging sensation coupled with erythema and edema. Photo-excitation of protoporphyrin in the skin leads to the painful photosensitivity characteristic of the disease. Increased biliary protoporphyrin excretion exerts toxic effects on hepatobiliary structure and function, although advanced, progressive liver disease manifests in only a small minority. It has been estimated that 10% of patients with severe protoporphyria experience clinically evident hepatic injury that progresses to hepatic fibrosis and, ultimately, hepatic failure. Once hepatic decompensation occurs, the disease progresses rapidly to death unless hepatic transplantation is accomplished.

Hepatic accumulation of protoporphyrin can be reduced but not eliminated by the administration of oral charcoal, cholestyramine, or colestipol. Additional measures that have been used include frequent red blood cell transfusions to suppress erythropoiesis, administration of hematin to suppress porphyrin synthesis, and plasmapheresis to remove free protoporphyrin in plasma. Liver transplantation is the only treatment with a long-lasting effect for patients with protoporphyria that have advanced liver disease.

When liver transplantation is used as a lifesaving procedure in individuals with protoporphyria, the patient needs to be prepared for surgery with aggressive plasmapheresis to remove protoporphyrin from the blood, and the operating room must be modified to reduce light exposure to exposed tissues during the transplant procedure by using red lights, which do not activate the protoporphyrin in light-exposed tissues. Biliary complications after liver transplant are more common in this group of patients. Neuropathy, a well-documented manifestation of acute hepatic porphyrias, was seen in 16% of protoporphyria patients after liver transplantation.

The ideal theoretical therapy for protoporphyria with developing liver failure is a combined bone marrow and liver transplant procedure. Unfortunately, once the liver disease is sufficiently advanced to justify liver transplantation, there is insufficient time to perform a bone marrow transplant and allow the individual to recover normal hematological status before the liver transplant because of rapid progression of the liver disease. Protoporphyrin-induced liver disease recurs in the transplanted liver despite the reduction in hepatic protoporphyrin production as a result of the liver transplant. Persistent production of excess protoporphyrin by bone marrow results in recurrent photosensitivity and hepatic disease. This fact strongly supports sequential transplantation of the liver followed by a bone marrow transplant in patients with protoporphyria once early clinical hepatic involvement becomes manifest.

Deficits in Fatty Acid Metabolism

Urea Cycle Defects

Urea cycle disorders are inborn errors of ammonia detoxification/arginine synthesis resulting from defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme, and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1 in 8000. These disorders are inherited as autosomal recessive disorders except for ornithine transcarbamylase deficiency, which is inherited as an X-linked recessive disorder. No single mutation in any of these disorders has been shown to define the disease. Rather, a large number of different mutations have been identified for each disorder. Thus the diagnosis of a urea cycle defect relies on enzymatic assays of blood and urine for the metabolites that characterize each disorder. Patients present with hyperammonemia either shortly after birth (approximately 50%) or later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.

Liver transplantation for a urea cycle deficiency is essentially curative. Episodes of hyperammonemia no longer occur, dietary restriction is no longer necessary, and alternative pathway medications can be discontinued. It is important to note that liver transplantation does not correct the low levels of plasma arginine and citrulline present in individuals with carbamoyl phosphate synthetase deficiency or ornithine transcarbamylase deficiency because most of the citrulline in plasma is a product of intestinal rather than hepatic synthesis. Thus individuals with either of these two disorders, even after successful liver transplantation, continue to require supplements of either citrulline or arginine. Because the preexisting neurological damage appears not to reverse, it is essential to prevent endogenous catabolism and hyperammonemia before and during liver transplantation. Liver transplantation offers severely affected patients with urea cycle disorders a better alternative in terms of quality of life than medical treatment.

Cystic Fibrosis

Cystic fibrosis is an autosomal recessive multisystem disease, primarily affecting the lungs, pancreas, gastrointestinal tract, and liver. Because of improvement in managing respiratory complications, liver disease has emerged as a significant medical issue. Focal biliary cirrhosis is the pathognomonic hepatic manifestation and results from biliary obstruction and progressive periportal fibrosis over time. Focal biliary cirrhosis can progress to multilobular cirrhosis with clinically significant portal hypertension and related complications.

Severe liver disease affects 4.5% to 10% of individuals with cystic fibrosis and is the third most common cause of death. Liver transplantation alone or combined liver and lung transplantation is an established treatment for patients with cystic fibrosis–related liver disease. Preferably, patients should undergo isolated liver transplantation before their lung function declines to a critical stage because combined liver-lung transplantation carries a worse prognosis. The overall survival rates after sole liver transplantation in adults and children were 85% and 90% at 1 year and 65% and 85% at 5 years, respectively. It has been suggested that patients with nutritional deterioration should undergo early and elective liver transplant because of association with worse outcome after liver transplant.