Transplantation for Hematological Disorders

Hereditary Amyloidosis

The most common genetic defect that causes systemic amyloid deposition derives from the transthyretin (TTR) gene, a mutation of which results in an autosomal dominant disease pattern. TTR, also called prealbumin , is a tetrameric plasma protein that transports thyroxin, triiodothyronine, and retinal binding protein. More than 80 TTR gene mutations have been identified as amyloidogenic (ATTR), the most common of which is a point mutation at amino acid 30 (V30M) in patients with familial amyloid polyneuropathy (FAP). Mutations result in altered TTR solubility, leading to deposition of insoluble amyloid fibers in the intracellular space and causing debilitating neuropathy and autonomic instability, impaired muscle contractility, restrictive cardiomyopathy with arrhythmias, renal failure, vitreal opacity, and severe gastrointestinal complications, including dysmotility, malabsorption, and bleeding. Patients may present with symptoms as early as 30 years of age, and the disease is often fatal within 10 years. About 95% of TTR is synthesized by the liver, the remaining 5% produced in the choroid plexus and retina. First used to halt disease progression, LT is now applied as a curative modality for ATTR, with an overall 1-year survival rate of 90% and a 5-year survival rate of 77%.

After LT greater than 95% of plasma TTR is wild-type ( Fig. 19-1 ), and a significant proportion of transplanted patients have regression of gastrointestinal symptoms (52%), sensory neuropathy (41%), motor and muscular function (37%), and improved nutritional status (40%). In a study of 33 FAP patients who underwent LT, renal failure stabilized, consistent with biopsy evidence showing no change in renal deposits. The data suggest that replacing the mutated TTR gene (in the transplanted liver) can reverse tissue injury secondary to amyloid deposition and that neuronal regeneration may occur. However, refractory intraoperative orthostatic hypotension and sudden cardiac death resulting from amyloid-induced conduction abnormalities may complicate the procedure, and only 21% of patients demonstrate improvement in cardiovascular symptoms. Persistent arrhythmias require close monitoring, and reversal of myocardial injury is problematic, as evidenced by the high rate of cardiac death (39%) versus that following LT for other indications (9%). In addition, some patients experience disease progression after LT, perhaps related to deposited amyloid serving as a nidus for further deposition of even wild-type TTR.

Given the 30 years or longer required for patients to develop symptoms attributable to amyloidosis, several domino liver transplants (DLTs) have been performed in which the explanted liver from the LT recipient with FAP is subsequently transplanted into a non-FAP patient (Domino Liver Transplant Registry, http://www.fapwtr.org/ram_domino.htm ). Amyloid deposits have been detected in biopsy autopsy specimens from asymptomatic DLT recipients of FAP livers. However, as of 2010, only three cases of neuropathy attributable to amyloidosis have been reported in recipients of DLTs at 7 to 9 years after transplant.

LT has been applied to treat other hereditary forms of amyloidosis in which the liver is the primary source of amyloid, as in the autosomal dominant form caused by mutation of the fibrinogen A-α chain. Because plasma fibrinogen derives overwhelmingly from hepatic synthesis, LT should be curative, and successful correction by LT has been documented in a single case report. LT has not been a viable therapeutic approach for the most common form of acquired systemic amyloidosis, caused by deposition of monoclonal immunoglobulin light-chain fragments produced by a malignant clone of plasma cells in the bone marrow.

Hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder linked to chromosome 6, with a 10% carrier rate and overall prevalence of 0.5%, notably in northern Europeans. A disruption in iron homeostasis leads to widespread tissue deposition, with clinical effects of cirrhosis, increased risk for hepatocellular carcinoma (HCC), cardiomyopathy, heart disease, arrhythmias, diabetes mellitus, skin hyperpigmentation, endocrine failure, and arthropathy. Clinical manifestations are highly variable, evolve slowly, are rarely present before the second decade, and are less evident in women who are protected by menstrual blood loss. Feder et al described two missense mutations (C282Y and H63D) in the HFE gene, which facilitates iron homeostasis via interaction of HFE protein with the transferrin receptor 1 ²¹ or by modulation of hepcidin synthesis. S65C is another commonly identified mutation in HFE. The HFE gene is expressed in the liver, but also in the intestines, pancreas, ovary, kidney, and placenta. The homozygous loss of cysteine in the C282Y mutation affects 80% to 90% of patients with clinical HH and prevents binding of the HFE protein to β ₂ -microglobulin, resulting in decreased expression of hepcidin and increased intestinal iron absorption. The H63D and S65C mutations convey some propensity for iron accumulation but do not have the same clinical impact as the C282Y mutation.

LT has provided insight into the pathogenesis of iron accumulation. Inadvertent transplant of a homozygous C282Y liver and intestine into a wild-type host resulted in iron overload, and LT of a C282Y heterozygous liver caused hemochromatosis, the recipient’s HFE genotype showing a novel C282Y/R6S compound heterozygous state. Even with transplantation of an affected liver, most cases do not show iron accumulation that is not explainable by concurrent medical illnes. About 50% to 75% of homozygous C282Y patients have clinical evidence of disease, classified into four stages, namely, genetic predisposition but no other abnormality, iron overload without symptoms, iron overload with early symptoms (lethargy, arthralgia), and iron overload with organ damage, especially cirrhosis. Before the discovery of the HFE gene the diagnosis of primary hemochromatosis was often based on the Hepatic Iron Index (hepatic iron concentration divided by age), a value greater than 1.9 defining HH. However, a review of more than 450 LT patients showed that only 10% of patients with a hepatic iron index of greater than 1.9 were homozygous for the C282Y mutation. Other inherited disorders of iron metabolism cause severe iron loading, including juvenile hemochromatosis resulting from mutations in hemojuvelin or hepcidin and mutations in the ferroporitin and transferrin receptor 2 genes.

Acquired (secondary) iron overload also leads to substantial hepatic iron deposition, perhaps as a by-product of inflammation or viral infection. Phlebotomy and chelator therapy before significant systemic iron deposition occurs can prevent clinical sequelae. Of 197 homozygous C282Y patients, none with a serum ferritin level of less than 1000 μg/L, normal aspartate aminotransferase level, or evidence of hepatomegaly had severe fibrosis, justifying conservative management without liver biopsy. In contrast, patients with clinical, radiographic, or biochemical markers consistent with substantial iron overload who are not homozygous for the C282Y mutation merit a diagnostic liver biopsy. Cardiac iron deposition can manifest as a dilated or restrictive cardiomyopathy with increased risk for arrhythmia, heart failure, and myocardial infarction, perhaps related directly to the HFE gene mutation itself. Increased iron load, regardless of cause, may contribute to atherosclerosis, and pretransplant iron depletion may improve post-LT survival.

HH accounts for only 0.5% to 1% of all LT cases. Decompensated liver disease is the main indication for LT, but because HH increases the risk for HCC by up to 200-fold, this is also considered in decisions for LT. For a group of 177 HH patients who underwent cadaveric LT in the United States from 1990 to 1996, survival rates were 79%, 72%, and 65% at 1, 3, and 5 years, slightly lower than in patients transplanted for other indications (86%, 80%, and 74%, respectively). However, among 217 patients undergoing LT between 1997 and 2006, survival rates were not significantly different than in other LT recipients. Younger subjects may have some degree of protection against subsequent iron deposition, but all HH patients are susceptible to bacterial and fungal infection, perhaps as a result of a deleterious effect of iron on cellular immunity. By biochemical measures, results of LT have been gratifying. A review of 22 HH patients who underwent LT showed that serum markers remained normal for 2.8 years. Early hepatic biopsy in 41 patients with pretransplant hemochromatosis showed no statistical difference in iron deposition in the new liver from that of a control population, and 2 of 3 C282Y homozygous patients had no iron accumulation. One report found no evidence of hepatic iron accumulation 11 to 111 months after LT in four C282Y homozygous transplant recipients.

As to long-term outcomes after LT, the underlying disorder is the principal determinant of success. Patients with secondary hemochromatosis have temporary relief of liver disease, but ultimately, recurrent iron accumulation may follow if the primary disorder is not corrected. For the HH patient, the post-LT course depends upon whether the hereditary defect affects HFE protein synthesis in the liver or in other organs ( Fig. 19-2 ). Absent irreversible cardiac disease, the patient with a mutation affecting hepatic synthesis should have an excellent response to LT. The hepatocytes of the allograft would produce a wild-type HFE protein that should correctly regulate iron homeostasis, thereby preventing further abnormal iron accumulation. However, if the primary defect stems from aberrant HFE proteins made in the duodenal mucosa, than LT would only serve to palliate, because pathological iron accumulation would not be controlled and recurrence of hepatic iron deposition and hepatic failure would follow.

Hemophilia

Hemophilia results from an X-linked deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B). Hemophiliacs who received clotting factor concentrates prepared from pooled human plasma before the mid 1980s were almost invariably exposed to the hepatitis C virus and the human immunodeficiency virus (HIV). The cumulative risk for hepatic decompensation in hemophiliacs with hepatitis C is 1.7% in 10 years and 10.8% in 20 years, and 30% of patients with persistent hepatitis develop cirrhosis. Hemophiliac patients with hepatitis C are often coinfected with HIV, a combination that increases the risk for substantial hepatic injury.

Liver transplantation has two values in the hemophiliac patient ( Fig. 19-3 ), serving as a lifesaving treatment for cirrhosis or HCC and as a potentially curative modality for hemophiliac bleeding. The first liver transplant in a patient with hemophilia A and end-stage liver disease was performed in 1985, with allograft function maintaining plasma factor VIII levels in the normal range by 18 hours after surgery; these findings were reproduced in a patient with hemophilia B in 1987.

Of 26 patients with hemophilia who underwent LT for liver failure between 1982 and 1996, all had their underlying factor deficiency corrected, replacement infusions being discontinued at 24 hours after surgery, coincident with the onset of de novo factor production. One- and 3-year survival rates were 83% and 68%, respectively, similar to data for nonhemophiliac patients who underwent LT for hepatitis. Survival rates for patients with HIV were significantly lower than for patients without HIV, 67% versus 90% at 1 year and 23% versus 83% at 3 years. Hemophiliac patients are at risk for recurrent hepatitis, noted in 6 of 20 patients at 9 months after being transplanted for hepatitis C after a mean of 9 months.

Hemostasis should not be a problem for hemophiliac patients undergoing LT, providing that appropriate factor replacement is administered to achieve blood levels of 100% during surgery and until healing, at approximately 14 days. Patients with a factor VIII inhibitor require special clotting factor management, including use of “bypass” agents (recombinant factor VIIa or prothrombin complex concentrate) and antifibrinolytic agents (ε-aminocaproic acid or tranexamic acid).

Because all of the vitamin K–dependent clotting factors (II, VII, IX, and X) are synthesized in hepatocytes, transplantation should cure such hereditary deficiencies, as documented in twin sisters with factor VII deficiency and severe bleeding symptoms who underwent LT. In a patient with factor XI deficiency who was transplanted for HCC and hepatitis C cirrhosis, LT corrected the factor XI level within 7 days of transplantation, implicating hepatocytes as a major site of factor XI synthesis. LT has also been used for correction of bleeding in patients with severe von Willebrand’s disease. Conversely, case reports show that factor deficiency may be acquired by LT from donors with hereditary deficiency of a specific clotting factor (see Liver Transplantation–Acquired Disorders).