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BACKGROUND AND AIMS: Severity of fibrosis is the driver of liver-related outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD), and non-invasive testing such as fibrosis-4 (FIB-4) score is utilized for risk stratification. We aimed to determine if primary care patients at risk for MASLD and advanced fibrosis were evaluated with subsequent testing. A secondary aim was to determine if at-risk patients with normal aminotransferases had advanced fibrosis. METHODS: Primary care patients at increased risk for MASLD with advanced fibrosis (n = 91,914) were identified using previously established criteria. Patients with known alternative/concomitant etiology of liver disease or cirrhosis were excluded. The study cohort included patients with calculated FIB-4 score in 2020 (n = 52,006), and stratified into low, indeterminate, and high likelihood of advanced fibrosis. Among those at indeterminate/high risk, rates of subsequent testing were measured. RESULTS: Risk stratification with FIB-4 characterized 77% (n = 40,026) as low risk, 17% (n = 8847) as indeterminate, and 6% (n = 3133) as high risk. Among indeterminate/high-risk patients (n = 11,980), 78.7% (n = 9433) had aminotransferases within normal limits, 0.95% (n = 114) had elastography, and 8.2% (n = 984) were referred for subspecialty evaluation. CONCLUSION: In this cohort of primary care patients at risk for MASLD with fibrosis, the FIB-4 score identified a substantial proportion of indeterminate/high-risk patients, the majority of which had normal aminotransferase levels. Low rates of subsequent testing were observed. These data suggest that a majority of patients at increased risk for liver-related outcomes remain unrecognized and highlight opportunities to facilitate their identification.
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INTRODUCTION: Diagnosis of drug-induced liver injury (DILI) is difficult. We reviewed cases in the DILI Network prospective study that were adjudicated to have liver injury due to other causes to discover pearls for improved diagnostic accuracy. METHODS: Cases were adjudicated by expert opinion and scored from 1 (definite DILI) to 5 (unlikely DILI). Confirmed cases (1-3) were compared with unlikely cases (5). RESULTS: One hundred thirty-four of the 1,916 cases (7%) were unlikely DILI. Alternative diagnoses were autoimmune hepatitis (20%), hepatitis C (20%), bile duct pathology (13%), and hepatitis E (8%). DISCUSSION: Thorough evaluation, including follow-up, is essential to minimize incorrect diagnosis of idiosyncratic DILI.
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Doença Hepática Induzida por Substâncias e Drogas , Hepatite C , Humanos , Estudos Prospectivos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/patologia , Hepatite C/patologia , CausalidadeRESUMO
Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.
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Dermatite Fototóxica , Doenças Genéticas Ligadas ao Cromossomo X , Hepatopatias , Guias de Prática Clínica como Assunto , Protoporfiria Eritropoética , Humanos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Protoporfiria Eritropoética/diagnóstico , Protoporfiria Eritropoética/genética , Protoporfiria Eritropoética/terapiaRESUMO
BACKGROUND: The coronavirus 2019 (COVID-19) pandemic required an immediate and large-scale transition to telemedicine. Telemedicine includes phone visits and video visits. Studies suggest that hepatocellular cancer (HCC) screening rates fell at the beginning of the COVID-19 pandemic. If left unaddressed, HCC morbidity/mortality may increase following the pandemic due to inadequate screening. AIMS: To assess the impact of phone-only visits on HCC screening rates in patients with cirrhosis. METHODS: Utilizing ICD-10 codes, 2 cohorts of patients with cirrhosis were identified. The pre-pandemic cohort had index visit between 1/1/2019 and 6/30/2019 (n = 290). The pandemic cohort (n = 112) was evaluated between 4/7/2020 and 6/7/2020. Each cohort was followed for 6 months from their index visit to determine HCC screening rate. Demographics and socioeconomic data from the American Community Survey database were compiled and compared between the cohorts. RESULTS: HCC screening rates in the pre-pandemic and pandemic cohorts were 72.4% and 69.6%, respectively, p = 0.67. No differences in HCC screening rates were observed between the two cohorts when stratified by demographic and socioeconomic factors. CONCLUSIONS: Use of phone-only visits was associated with adherence to HCC screening similar to that seen with in-person visits. The lack of influence on screening rates by racial/socioeconomic factors suggest telephone-only visits do not exacerbate healthcare disparities. In times of public health of crisis, telephone-only visits may provide the necessary access to hepatology care to ensure HCC screening regimens remain in-place for at-risk patients.
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COVID-19 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Telemedicina , Humanos , Detecção Precoce de Câncer , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Pandemias , COVID-19/epidemiologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , TelefoneRESUMO
BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.
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Hepatite C Crônica , Porfiria Cutânea Tardia , Porfirinas , Masculino , Humanos , Feminino , Sofosbuvir/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Porfiria Cutânea Tardia/diagnóstico , Porfiria Cutânea Tardia/tratamento farmacológico , Porfiria Cutânea Tardia/induzido quimicamente , Fluorenos/uso terapêutico , Hepacivirus/genética , Resultado do Tratamento , Quimioterapia Combinada , RNA , Genótipo , Porfirinas/farmacologia , Porfirinas/uso terapêuticoRESUMO
Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.
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Doenças do Sistema Nervoso Periférico/mortalidade , Doenças do Sistema Nervoso Periférico/patologia , Polineuropatias , Sintase do Porfobilinogênio/deficiência , Porfirias Hepáticas/mortalidade , Porfirias Hepáticas/patologia , Ácido Aminolevulínico/metabolismo , Síndrome de Guillain-Barré/mortalidade , Síndrome de Guillain-Barré/patologia , Humanos , Doenças do Sistema Nervoso Periférico/diagnóstico , Polineuropatias/mortalidade , Polineuropatias/patologia , Nervo Radial/patologiaRESUMO
The acute hepatic porphyrias include four disorders: acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], and the rare porphyria due to severe deficiency of ALA dehydratase [ADP]. In the USA, AIP is the most severe and most often symptomatic. AIP, HCP, and VP are due to autosomal dominant genetic abnormalities, in which missense, nonsense, or other mutations of genes of normal hepatic heme biosynthesis, in concert with other environmental, nutritional, hormonal and genetic factors, may lead to a critical deficiency of heme, the end-product of the pathway, in a small but critical 'regulatory pool' within hepatocytes. This deficiency leads to de-repression of the first and normally rate-controlling enzyme of the heme synthetic pathway, delta- or 5-aminolevulinic acid [ALA] synthase-1, and thus to marked up-regulation of this key enzyme and to marked hepatic overproduction of ALA. In addition, except for ADP, there is marked overproduction as well of porphobilinogen [PBG], the intermediate immediately downstream of ALA in the synthetic chain, and, especially in HCP and VP, also porphyrinogens and porphyrins farther down the pathway. The major clinical features of the acute porphyrias are attacks of severe neuropathic-type pain. Pain is felt first and foremost in the abdomen but may also occur in the back, chest, and extremities. Attacks are more common in women than in men [ratio of about 4:1], often accompanied by nausea, vomiting, constipation, tachycardia, and arterial hypertension. Hyponatremia may also occur. Some patients also describe chronic symptoms of pain, anxiety, insomnia, and others.
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Heme/biossíntese , Sintase do Porfobilinogênio/deficiência , Porfirias Hepáticas/genética , Ansiedade/etiologia , Heme/genética , Humanos , Mutação , Neuralgia/etiologia , Porfobilinogênio , Sintase do Porfobilinogênio/classificação , Sintase do Porfobilinogênio/genética , Porfirias Hepáticas/classificação , Porfirias Hepáticas/complicações , Distúrbios do Início e da Manutenção do Sono/etiologiaRESUMO
BACKGROUND AND AIMS: The acute porphyrias are characterized by defects in heme synthesis, particularly in the liver. In some affected patients, there occurs a critical deficiency in a regulatory heme pool within hepatocytes that leads to up-regulation of 5-aminolevulinic acid [ALA] synthase-1, which is the first and normally rate-controlling enzyme in the pathway. In earlier work, we described defects in mitochondrial functions in cultured skin fibroblasts from patients with acute intermittent porphyria [AIP]. Others described defects in livers of murine models of AIP. Here, we explored mitochondrial energetics in peripheral blood mononuclear cells [PBMCs] and platelets in persons with AIP and hereditary coproporphyria [HCP]. Our hypotheses were that there are deficits in bioenergetic capacity in acute porphyrias and that subjects with more severe acute porphyria have more pronounced reductions in mitochondrial oxygen consumption rates [OCR]. METHODS: We studied 17 subjects with acute hepatic porphyrias, 14 with classical AIP, one with severe AIP due to homozygous deficiency of hydroxymethylbilane synthase [HMBS], 2 with HCP, and 5 non-porphyric controls. We collected peripheral blood, isolated PBMCs, which we assayed either immediately or after frozen storage [80C] for up to 14â¯days. Using Seahorse XF-24-3, we measured OCR in the presence of glucose + pyruvate under basal condition, and after additions of oligomycin, carbonylcyanide p-trifluoromethoxyphenylhydrazone [FCCP], and antimycin+rotenone. RESULTS: Most subjects [13/17, 76%] were female. Subjects with moderate/severe symptoms associated with acute porphyria had significantly lower basal and maximal-OCR than those with no/mild symptoms who were the same as controls. We observed significant inverse correlation between urinary porphobilinogen [PBG] excretion and OCR. The subject with homozygous AIP had a much lower-OCR than his asymptomatic parents. SUMMARY/CONCLUSIONS: Results support the hypothesis that active acute hepatic porphyria is characterized by a deficiency in mitochondrial function that is detectable in PBMCs, suggesting that limitations in electron transport and ATP production exist in such individuals.
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Coproporfiria Hereditária/sangue , Metabolismo Energético , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Oxigênio/metabolismo , Trifosfato de Adenosina/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Plaquetas/patologia , Coproporfiria Hereditária/patologia , Transporte de Elétrons , Feminino , Heme/biossíntese , Humanos , Lactente , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Porfiria Aguda Intermitente/sangue , Porfiria Aguda Intermitente/patologiaRESUMO
INTRODUCTION: The aim of this study is to investigate large volume therapeutic paracentesis using either a z-tract or axial (coxial) technique in a randomized controlled trial. MATERIALS AND METHODS: In this randomized, single blind study, patients with cirrhosis undergoing outpatient therapeutic paracentesis were randomized to the z-tract or the modified angular (coaxial) needle insertion technique. Subject and procedure characteristics were compared between the groups with ascites leakage as quantified by need for dressing changes with standardized sized gauze pads as a primary endpoint and subject procedural discomfort, operator preference, and procedure complications as secondary endpoints. RESULTS: 72 paracenteses were performed during the study period: 34 to the z-tract and 38 to the coaxial insertion technique. Following exclusions, a total of 61 paracenteses were analyzed: 30 using the z-tract technique and 31 using the coaxial technique. There were equal rates of post-procedural leakage of ascites between groups (13% in both groups, p = 1.00). Using the visual analog scale (0 - 100), there was a statistically significant increase in the subject reported pain score with the z-tract compared with the coaxial method [26.4 (95% CI 18.7 - 34.1) vs. 17.2 (95% CI 10.6 - 23.8), p = 0.04]. Mean physician rated procedure difficulty (1 - 5) was significantly higher for the z-tract versus the coaxial technique [2.1 (95% CI 1.6 - 2.6) vs. 1.5 (95% CI 1.2 - 1.8), p = 0.04]. CONCLUSION: When compared to the z-tract technique, the coaxial insertion technique is superior during large volume paracentesis in cirrhosis patients.
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Ascite/terapia , Cirrose Hepática/complicações , Paracentese/métodos , Assistência Ambulatorial , Ascite/diagnóstico , Ascite/etiologia , Feminino , Hospitais Universitários , Humanos , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Paracentese/efeitos adversos , Método Simples-Cego , Resultado do Tratamento , VirginiaRESUMO
Background: Porphyria cutanea tarda (PCT) is usually caused by acquired defects in uroporphyrinogen decarboxylase (UROD) activity in the liver. This more common form of PCT is called type 1 PCT. Major known risk factors for PCT include iron overload, such as occurs due to mutations in HFE, associated with classical hereditary hemochromatosis, chronic hepatitis C infection, heavy alcohol use, tobacco use, and estrogen therapy. In addition, in about 25% of patients with PCT, namely, those with PCT type 2, an inherited partial defect in UROD activity is found. In such persons, this partial defect, which is found in all cells, including hepatocytes, red blood cells, and others, contributes to the development of biochemically and clinically active disease. Case Description: Herein we describe salient features of a man in his eighth decade of life with onset of clinical PCT. Among risk factors were heavy alcohol and tobacco use. Genetic testing revealed a novel mutation in one of his alleles of the UROD gene, namely, c.224 G>C; p. Arg 75 Pro, and enzymatic testing revealed that red blood cell UROD activity was decreased by 50%. This mutation in the UROD gene is predicted to have a major effect on protein structure and function, confirmed by the 50% decrease in activity of the enzyme. Conclusions: The previously undescribed mutation in UROD, found in this man, namely, c.224 G>C; p. Arg 75 Pro is pathogenic.
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Erythropoietic protoporphyria (EPP) is a genetic disorder stemming from reduced ferrochelatase expression, the final enzyme in the pathway of heme biosynthesis. A closely related condition, X-linked protoporphyria (XLP), bears similar clinical features although it arises from the heightened activity of δ-aminolevulinic acid synthase 2 (ALAS2), the first and normally rate-controlling enzyme in heme biosynthesis in developing red blood cells. Both of these abnormalities result in the buildup of protoporphyrin IX, leading to excruciating light sensitivity and, in a minority of cases, potentially fatal liver complications. Traditionally, managing EPP and XLP involved sun avoidance. However, the emergence of innovative therapies, such as dersimelagon, is reshaping the therapeutic landscape for these conditions. In this review, we summarize salient features of the properties of dersimelagon, shedding light on its potential role in advancing our understanding of treatment options for EPP and XLP.
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Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Acute hepatic porphyrias are a group of rare, inherited metabolic disorders, characterized by acute potentially life-threatening attacks as well as chronic symptoms with a negative impact on quality of life. It has four types, each associated with distinct enzyme defects in the heme biosynthesis pathway in the liver. By targeting the expression of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1], givosiran can down-regulate levels of toxic metabolites, leading to biochemical and clinical improvement. Givosiran selectively targets hepatocytes due to its linkage to N-acetylgalactosamine (GalNac) leading to its selective uptake via asialoglycoprotein receptors (ASGPR). We provide an up-to-date literature review regarding givosiran in the context of a clinical overview of the porphyrias, an overview of siRNAs for therapy of human disorders, the design and development of givosiran, key clinical trial results of givosiran for prevention of acute porphyric attacks, emerging concerns regarding chronic use of givosiran, and the overall management of acute hepatic porphyrias. These insights are important not only for the management of acute hepatic porphyrias but also for the emerging field of siRNAs and their role in novel therapies for various diseases.
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Acetilgalactosamina , Porfirias Hepáticas , Acetilgalactosamina/análogos & derivados , Acetilgalactosamina/uso terapêutico , Adulto , Humanos , Sintase do Porfobilinogênio/deficiência , Porfirias Hepáticas/diagnóstico , Porfirias Hepáticas/tratamento farmacológico , Porfirias Hepáticas/genética , Pirrolidinas , Qualidade de Vida , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/uso terapêuticoRESUMO
Management of decompensated cirrhosis (DC) can be challenging for the surgical intensivist. Management of DC is often complicated by ascites, coagulopathy, hepatic encephalopathy, gastrointestinal bleeding, hepatorenal syndrome, and difficulty assessing volume status. This Clinical Consensus Document created by the American Association for the Surgery of Trauma Critical Care Committee reviews practical clinical questions about the critical care management of patients with DC to facilitate best practices by the bedside provider.
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The diagnosis and management of cirrhosis and portal hypertension (PH) with its complications including variceal hemorrhage, ascites, and hepatic encephalopathy continues to evolve. Although there are established "standards of care" in liver biopsy and measurement of PH, gastric varices remain an area without a universally accepted therapeutic approach. The concept of "Endo Hepatology" has been used to describe of the applications of endoscopic ultrasound (EUS) to these challenges. EUS-liver biopsy (EUS-LB) offers an alternative to percutaneous and transjuglar liver biopsy without compromising safety or efficacy, and with added advantages including the potential to reduce sampling error by allowing biopsies in both hepatic lobes. Furthermore, EUS-LB can be performed during the same procedure as EUS-guided portal pressure gradient (PPG) measurements, allowing for the collection of valuable diagnostic and prognostic data. EUS-guided PPG measurements provide an appealing alternative to the transjugular approach, with proposed advantages including the ability to directly measure portal vein pressure. In addition, EUS-guided treatment of gastric varices (GV) offers several possible advantages to current therapies. EUS-guided treatment of GV allows detailed assessment of the vascular anatomy, similar efficacy and safety to current therapies, and allows the evaluation of treatment effect through doppler ultrasound visualization. The appropriate selection of patients for these procedures is paramount to ensuring generation of useful clinical data and patient safety.
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The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%-3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long-term complications. Their first-degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down-regulate ALA synthase-1 and/or wild-type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders.
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Acute intermittent porphyria (AIP), an autosomal dominant inborn error of metabolism, is the most common and severe form of the acute porphyrias. Attacks of severe abdominal pain, often with hypertension, tachycardia, are cardinal features of AIP, often requiring hospital admissions. Frequent recurrent attacks of AIP, defined as >3 attacks in one year, during which at least one attack requires intravenous heme therapy, are associated with significant morbidity, lost productivity, and health care burden. We report two patients with such frequent attacks of AIP, who have been managed with prophylactic heme therapy on a weekly basis. We describe results particularly in relation to symptom control, biochemical findings, health care costs, quality of life, and utilization of resources. During 11-month duration of weekly prophylactic heme infusions, we observed a 100% decrease in acute attacks and inpatient admissions in one subject and a 75% decrease in the other. During this time, we also observed a significant decrease in the number of emergency room visits. The decrease in number of acute attacks requiring hospital admission was associated with significantly decreased health care costs and improved quality of life. Reduction of both emergency room visits and hospital admissions decreased the utilization of health care services. Outpatient weekly infusions were also noted to be associated with better reimbursements and reduced overall costs of health care for the subjects. Both our subjects also endorsed better symptom control, quality of life and better understanding of disease. Thus, prophylactic heme therapy, through a multi-disciplinary approach, decreases the incidence of acute attacks, decreases health care costs and leads to better patient satisfaction and quality of life.
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INTRODUCTION: Unresectable hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT). The Milan criteria became standard criteria but expansion beyond the Milan criteria (tumor size and number) have resulted in similar post-transplant outcomes, thus suggesting LT is a viable treatment option for HCC presenting beyond the Milan criteria Areas covered: Expanded criteria and the use of downstaging therapies to meet Milan criteria are reviewed. Surrogates of tumor biology (including biomarkers and response to therapy) are described in detail. The controversy regarding treatment of HCV infection prior to transplant for HCC is addressed. Predictors of post-transplant recurrence and therapeutic options are explored. English-language manuscripts pertaining to LT criteria for HCC, downstaging, and tumor prognosis were reviewed. Effort was made to include manuscripts from throughout the world to ensure the reader a broad international perspective. Expert commentary: Patients can be successfully transplanted with HCC beyond Milan criteria, or patients beyond Milan criteria can be downstaged to within Milan criteria and achieve successful post-liver transplant outcomes. The current reliance on tumor burden (size and number) alone ignores the mounting data supporting the prognostic use of additional surrogates of tumor biology in identifying appropriate candidates.