Long-term outcomes and trends in liver transplantation for hereditary hemochromatosis in the United States.

There have been conflicting data regarding liver transplantation (LT) outcomes for hereditary hemochromatosis (HH), with no recent data on LT outcomes in patients with HH in the past decade. Using the United Network for Organ Sharing registry, we evaluated waitlist and post-LT survival in all adult patients listed for HH without concomitant liver disease from 2003 to 2019. Post-LT survival for HH was compared with a propensity-matched (recipient and donor factors) cohort of recipients with chronic liver disease (CLD). From 2003 to 2019, 862 patients with HH were listed for LT, of which 55.6% ( n = 479) patients underwent LT. The 1- and 5-year post-LT survival rates in patients with HH were 88.7% (95% confidence interval [CI], 85.4%-91.4%) and 77.5% (95% CI, 72.8%-81.4%), respectively, and were comparable with those in the propensity-matched CLD cohort ( p value = 0.96). Post-LT survival for HH was lower than for Wilson's disease, another hereditary metabolic liver disease with similar LT volume ( n = 365). Predictors for long-term (5-year) post-LT mortality included presence of portal vein thrombosis (hazard ratio [HR], 1.96; 95% CI, 1.07-3.58), obesity measurements greater than Class II (HR, 1.98; 95% CI, 1.16-3.39), and Karnofsky performance status (HR, 0.98; 95% CI, 0.97-0.99) at the time of LT. The leading cause of post-LT death ( n = 145) was malignancy (25.5%), whereas cardiac disease was the cause in less than 10% of recipients. In conclusion, short- and long-term survival rates for HH are excellent and comparable with those of other LT recipients. Improving extrahepatic metabolic factors and functional status in patients with HH prior to LT may improve outcomes.

Mechanical sensitivity of red blood cells improves in individuals with hemochromatosis following venesection therapy.

BACKGROUND: Individuals with hereditary hemochromatosis (HH) receive frequent blood withdrawals (ie, venesections) as part of their primary treatment to assist in normalizing blood iron levels. It remains unclear whether this source of blood is suitable for use in blood product development, as current data indicate that red blood cell (RBC) deformability, both before and after shear stress exposure, is impaired in individuals with HH, relative to healthy controls. Given that venesection therapy is known to significantly reduce circulating iron levels in individuals with HH, the current study examined whether venesection therapy is effective at improving RBC mechanical properties, both before and after shear stress exposure, in individuals with HH. STUDY DESIGN AND METHODS: Blood samples were initially collected from untreated HH patients (age, 61 ± 9 years; 14% female) undergoing their first venesection, and then again during their second (approx. 9 weeks later) and third (approx. 16 weeks later) venesections. RBC deformability was measured at each time point with a commercial ektacytometer. Moreover, to determine cell responses to mechanical stimuli, the mechanical sensitivity of blood samples was determined at each time point. RESULTS: The salient findings indicate that venesection therapy used for managing plasma ferritin concentration significantly improves the cellular deformability of RBC in individuals with HH. Further, the sensitivity of RBC to supraphysiological mechanical stress is decreased (ie, improved) in a dose-response fashion with routine venesection. CONCLUSION: While cellular mechanics of RBC from individuals with HH are impaired when untreated, venesection therapy significantly improves cellular properties of RBC, supporting the use of venesections in blood product development from individuals with well-managed HH.

Contemporary Total Hip and Total Knee Arthroplasty Results in Patients with Hemochromatosis.

BACKGROUND: Hemochromatosis can result in metabolic bone pathology (due to excessive iron absorption) and degenerative joint disease, leading to total joint arthroplasties. The aim of this study is to analyze the survivorship, complications, radiographic results, and clinical outcomes of patients with hemochromatosis who received either a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). METHODS: We identified 34 lower extremity arthroplasties in 29 patients with hemochromatosis performed between 2000 and 2016. There were 17 primary THAs in 15 patients and 17 primary TKAs in 14 patients. Mean age at arthroplasty was 63 years with 76% being male. The mean body mass index was 28 kg/m2. Mean follow-up was 5 years. RESULTS: The survivorship free from any revision for THAs was 94% at 10 years. One patient was revised for aseptic loosening of the femoral stem at 6 months. In THA patients, no infections, no other complications, and no radiographic evidence of aseptic loosening were identified. Harris Hip Scores improved from a mean of 55 preoperatively to 94 postoperatively (P < .001). The survivorship free from any revision for TKAs was 100% at 10 years. Two patients (12%) developed acquired idiopathic stiffness postoperatively; no infections were identified. There was no radiographic evidence of aseptic loosening in any TKA. Knee Society Scores improved from a mean of 61 preoperatively to 94 postoperatively (P < .001). CONCLUSION: This study found excellent survivorship, significant improvements in clinical outcomes, and a very low complication profile for both THA and TKA in patients with hemochromatosis.

Nonrheumatoid Arthritis of the Hand.

Arthropathy of the hand is commonly encountered. Contributing factors such as aging, trauma, and systemic illness all may have a role in the evolution of this pathology. Besides rheumatoid arthritis, other diseases affect the small joints of the hand. A review of nonrheumatoid hand arthropathies is beneficial for clinicians to recognize these problems.

Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis.

UNLABELLED: Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE-related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (± 99) µg/L. Magnetic resonance imaging showed that iron overload was absent in nine patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis discovered after LT. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. CONCLUSION: In HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients who received LTs for other liver diseases.

Liver transplantation for neonatal hemochromatosis: analysis of the UNOS database.

NH is the most common identifiable cause of ALF in the neonate. LT is the definitive treatment for neonates with NH who have failed medical therapy. Our aim was to determine the outcomes of LT in infants with NH. Patients (less than one yr of age) with NH who were listed for LT and patients who underwent LT between 1994 and 2013 were identified from the UNOS database for analysis. Risk factors for death and graft loss were analyzed by multivariate logistic regression. Thirty-eight infants with NH with a total of 43 transplants were identified. One- and five-yr patient and graft survival were 84.2%, 81.6%, 71.1%, and 68.4%, respectively. The outcomes for NH were not significantly different when compared to the same age-matched recipients with other causes of ALF. There were no statistically significant risk factors identified for graft loss or death. Ninety infants with NH were listed for LT. Reasons for removal included transplanted (49%), death (27%), too sick to transplant (7%), and improved status (13%). LT for infants with NH has a high rate of graft loss and death; however, outcomes are comparable to the same age-matched recipients with other causes of ALF.

A Matched-Cohort Analysis of Outcomes in Patients with Hereditary Hemochromatosis After Anterior Cervical Discectomy and Fusion.

BACKGROUND: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder. This disease affects gut iron transport, leading to iron overload, which affects immune function, coagulation mechanics, and bone health. Within the spine, HH contributes to decreased bone mineral density and accelerated intervertebral disc degeneration. The purpose of this study was to discover the differences in the rates of common 90-day postoperative complications and 1-year and 2-year surgical outcomes in patients with and without HH after anterior cervical discectomy and fusion (ACDF). METHODS: Using the PearlDiver database, patients with active diagnoses of HH before ACDF were matched to patients without HH using a 1:5 ratio on the basis of age, sex, body mass index, and comorbidities. Postoperative complications were assessed at 90 days, and 1-year and 2-year surgical outcomes were assessed. All outcomes and complications were analyzed using multivariate logistic regression with significance achieved at P < 0.05. RESULTS: Patients with HH had significantly higher rates of 1-year and 2-year reoperation rates compared with patients without HH (29.19% vs. 3.94% and 37.1% vs. 5.93%, respectively; P < 0.001). The rates of 90-day postoperative complications significantly increased in patients with HH including dysphagia, pneumonia, cerebrovascular accident, deep vein thrombosis, acute kidney injury, urinary tract infection, hyponatremia, surgical site infection, iatrogenic deformity, emergency department visit, and hospital readmission. CONCLUSIONS: Patients with HH undergoing ACDF showed increased 90-day postoperative complications and significantly increased rates of 1-year and 2-year reoperation compared with patients without HH. These findings suggest that iron overload may contribute to adverse outcomes in patients with HH undergoing 1-level and 2-level ACDF.

Primary biliary cirrhosis-specific antimitochondrial antibodies in neonatal haemochromatosis.

BACKGROUND AND AIM: Neonatal hemochromatosis (NH) is characterised by severe liver injury and extrahepatic siderosis sparing the reticuloendothelial system. Its aetiology is obscure, although it has been proposed as an alloimmune disease, resulting from immunological reaction to self-antigens (alloantigens) which the body recognizes as foreign. We studied an infant with NH and his mother whose sera contained antimitochondrial antibody (AMA), the hallmark of primary biliary cirrhosis (PBC). MATERIAL AND METHODS: To investigate the origin of AMA in the infant, we studied isotype distributions in serum from the mother and infant. Serum samples were obtained at diagnosis of NH, after liver transplantation (LT; age 1 month), and over the ensuing 17 months. RESULTS: At NH diagnosis, infant and maternal serum contained AMA of the IgG isotype, predominantly of the G3 and G1 subclasses. AMA strongly reacted against the pyruvate dehydrogenase complex E2 subunit (PDC-E2), the major PBC-specific AMA autoantigen. Anti-PDC-E2 responses in both infant and mother declined over time, being present 2 months after LT (mother and child) and absent 10 months later (mother) and 17 months later (child). CONCLUSION: The association of maternally transferred IgG1 and IgG3 subclass AMA with the appearance of liver damage in an infant with NH may suggest a causal link between antibody and liver damage.

Increased rates of spinal fusion surgery in patients with hereditary hemochromatosis: a five-year propensity matched cohort analysis.

OBJECT: Spinal arthropathy is associated with hereditary hemochromatosis and has been linked to calcium pyrophosphate dehydrate crystal deposition (CPPD) which resembles ankylosing spondylitis on radiograph, yet lacks clinical findings of inflammatory spinal arthritis. The aim of our study was to assess the use of spinal surgery and its outcomes in the US inpatient population with hereditary hemochromatosis from 2012 to 2016 by using the US Nationwide Inpatient Sample (NIS) database. METHODS: The observational retrospective cohort study uses the NIS 2012 to 2016. All patients with hereditary hemochromatosis were included using International Classification of Diseases 9th and 10th revisions, Clinical Modification codes. The cohort was stratified according to having undergone spinal surgery and substratified by the type of surgery. The primary outcome was determining the use of spinal surgery in patients with hereditary hemochromatosis. Secondary outcomes were determining length of hospital stay and total hospital charges and costs. RESULTS: A total of 39 780 patients with hereditary hemochromatosis were identified and propensity matched to nonhereditary hemochromatosis controls. The mean patient age was 61 years, and 65% were females. For the primary outcome patients with hereditary hemochromatosis underwent significantly more spinal fusion surgery compared to patients without hereditary hemochromatosis odds of 2.13 (P = 0.05). While there was no difference in mean LOS, or costs, patients with hereditary hemochromatosis had higher hospital charges. CONCLUSION: Hereditary hemochromatosis is associated with higher odds of spinal fusion. It is a major complication not improved by phlebotomy, and there are currently no therapies to prevent this joint disease.

Prevalence of genetic haemochromatosis and iron overload in patients attending rheumatology and joint replacement clinics.

BACKGROUND & AIMS: Genetic Haemochromatosis (GH) is common in North European and Celtic populations and is associated with arthropathy. We aimed to measure the frequency of the common GH mutations (C282Y and H63D), the carrier frequency of C282Y and markers of iron overload in patients who were referred to our rheumatology and joint replacement clinics. METHODS: Unselected patients attending these clinics were anonymously tested for the described mutations. Transferrin saturation and serum ferritin were also measured and if elevated, the patients had predictive counselling then named GH mutation testing. The carrier and mutation frequencies were also determined in 340 local controls. RESULTS: One hundred and sixty-one unselected patients attending these clinics were studied. The C282Y mutation carrier frequency was 1 in 5.2 in patients compared with 1 in 8.1 in controls (p < 0.005). The overall mutation frequencies were similar in patients and controls. One patient was found to be a homozygous for the C282Y mutation and eight were compound heterozygotes. Seven other patients had a raised ferritin, one of whom was a C282Y heterozygote. CONCLUSION: The C282Y carrier frequency is significantly higher in patients attending rheumatology and joint replacement clinics than in controls. Screening of these patients for GH should be considered.

Liver transplantation for inherited metabolic disorders of the liver.

PURPOSE OF REVIEW: Liver transplantation is curative, life saving or both for a range of inherited diseases affecting the liver. Indications, timing and outcome of transplantation for these diseases are the focus of this review. RECENT FINDINGS: Liver transplant represents a mode of gene replacement therapy for several disorders, including Wilson disease, hemochromatosis, tyrosinemia, urea cycle defects and hypercholesterolemia in which the primary defect residing in the liver results in hepatic complications or severe extrahepatic disease. Liver transplant is also an important therapeutic modality in multisystemic genetic disorders with major hepatic disease such as glycogen storage disease types I, III and IV and porphyria. For familial amyloidosis and primary hyperoxaluria, liver replacement eliminates the source of the injurious products that results in extrahepatic disease. Innovations in medical and surgical management of these patients have led to improved outcomes providing an important benchmark for future gene therapy of these disorders. SUMMARY: Recent developments have refined the indications for liver transplant in the treatment of inherited metabolic diseases. The full potential of liver transplant in these disorders can be harnessed by careful patient selection, optimizing timing and perioperative metabolic management of these patients.

Hereditary hemochromatosis is associated with increased use of joint replacement surgery: Results of a nationwide analysis.

BACKGROUND: Hereditary hemochromatosis (HH) may lead to iron deposition-mediated arthropathy, causing progressive joint degeneration, necessitating replacement arthroplasty. Studies have noted an increased need for replacement arthroplasty in patients with HH. We aimed to compare the use of replacement arthroplasty and inpatient economic burden in patients with and without HH. METHODS: For our retrospective cohort study, we used the 2014 Nationwide Inpatient Sample. Patients with an International Classification of Diseases, Ninth Revision code for HH were included. The primary outcome was use of replacement arthroplasty; secondary outcomes were hospital length of stay, hospital costs, and total hospitalization charges. Multivariate logistic regression yielded confounder-adjusted odds ratios (ORs) and means. RESULTS: Of 18,250 patients with HH, 7,483 (41.0%) were women and 1,155 (6.3%) underwent replacement arthroplasty. Mean (SD) age for patients with HH and arthroplasty was 66 (18) years. The percentage of patients with HH who underwent replacement arthroplasty was higher than those without HH (3.4%; P<.01). On multivariate analysis, young-adult females and elderly patients with HH were more likely to undergo replacement arthroplasty compared to those without HH of the corresponding gender and age group. Mean length of stay, hospital costs, and total hospitalization charges were increased only in young adult females. CONCLUSIONS: HH is associated with increased odds of replacement arthroplasty, particularly in the elderly, which can potentially suggest faster arthropathy progression in this age group and should raise awareness in clinicians taking care of patients with HH. Future research should identify factors mediating arthropathy progression in patients with HH.

Severe iron overload with a novel aminolevulinate synthase mutation and hepatitis C infection. A case report.

A 55 year old man with a history of chronic hepatitis C infection was found to have severe hemochromatosis: hepatic cirrhosis, cardiomyopathy, arrhythmia, hypogonadism, diabetes and bronzed skin color. After 50 phlebotomies, he underwent a combined heart and liver transplant. Genetic analyses identified a novel mutation in the iron responsive element of the ALAS2 gene. No mutations were found in other genes associated with adult or juvenile hemochromatosis including HFE, transferrin receptor-2 (TFR2), ferroportin (SLC40A1), hepcidin (HAMP) and hemojuvelin (HJV). We suggest that the ALAS2 mutation together with chronic hepatitis C infection may have caused the severe iron overload phenotype.

Overview: Liver disease and transplantation.

Australia has had a proud and enviable record of seminal contributions to hepatology, with many contributors. Thus, any attempt to summarize these contributions ab initio in a brief review article is a significant challenge, primarily because it is so easy to overlook or underestimate particular aspects. In this article, I have confined my comments primarily to the areas where the contributions have had a significant global impact and have clearly been recognized internationally. This means that many worthwhile Australian additions will be omitted if there was less apparent international impact. The first significant interest in liver disease in Australia was from the Melbourne group at the Walter and Eliza Hall Institute (WEHI) and Royal Melbourne Hospital, leading to seminal contributions to the description, diagnosis, aetiopathogenesis and therapy of autoimmune hepatitis and primary biliary cirrhosis. Others from Royal Prince Alfred Hospital in Sydney contributed substantially to the effects of immunosuppression of autoimmune hepatitis and to early descriptions of primary sclerosing cholangitis. Other areas where Australians have contributed significantly include steatohepatitis, iron metabolism (and in particular hemochromatosis), viral hepatitis (both at the molecular and clinical level), portal hypertension, and transplant immunology. The remarkable contribution of Professor Dame Sheila Sherlock to Australian hepatology is also summarized.

Molecular adsorbent recirculating system (Mars) in patients with primary nonfunction and other causes of graft dysfunction after liver transplantation in the era of extended criteria donor organs.

Liver dysfunction is an important cause of morbidity and mortality after orthotopic liver transplantation (OLT). The Molecular Adsorbent Recirculating System (MARS) is an albumin-based dialysis system designed to enhance the excretory function of a failing liver. MARS has been successfully used in patients affected by advanced liver disease and presenting with severe cholestasis. The aim of this study was to evaluate the safety and clinical efficacy of MARS in patients with liver dysfunction after OLT. Seven patients (primary nonfunction, 2 patients; graft dysfunction, 5 patients) fulfilled the inclusion criteria of serum bilirubin level >15 mg/dL and least 1 of the following clinical signs: hepatic encephalopathy (HE) > or = grade II, hepatorenal syndrome (HRS), and intractable pruritus. Graft and patient survival rates at 6 months were 42.8% and 57.1%, respectively. All patients tolerated MARS treatment, with no adverse event. In all patients, a decrease in serum bilirubin (P < .05), bile acids (P < .05), serum creatinine, and ammonia levels was observed after treatment with MARS. A considerable improvement of HE, as well as renal and synthetic liver functions, was observed in 4 of 5 patients with graft dysfunction, but not among those with primary nonfunction. The patients with intractable pruritus showed significant improvement of this symptom after MARS therapy. Thus, MARS is a safe, therapeutic option for the treatment of liver dysfunction after OLT. Further studies are necessary to confirm whether this treatment is able to improve both graft and patient survival.