Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. MATERIALS AND METHODS: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. RESULTS: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) µg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. CONCLUSIONS: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

A randomized trial of normothermic preservation in liver transplantation.

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.

Clinical and prognostic associations of liver volume determined by computed tomography in acute liver failure.

BACKGROUND: Liver volume (LV) can be non-invasively determined from the analysis of computed tomography (CT) images, and in patients with acute liver injury (ALI) or failure (ALF), it can reflect the balance of structural collapse with hepatic regeneration. We examined its relation to cause of liver injury, measures of liver function and histopathological findings, and utility in prediction of complications and mortality. METHODS: Two hundred and seventy-three patients with ALF/ALI admitted to a specialist intensive care unit were studied. One hundred and ninety-nine patients (73%) had non-acetaminophen (NA) aetiologies and 74 (27%) had acetaminophen-induced disease. LV and proportion of predicted LV (PLV%) were determined from admission CT imaging. RESULTS: LV and PLV% showed marked variation when aetiologic groups were compared (P < .0001), including loss in cases with indeterminate cause (LV 939 cm3 [IQR 680-1259], PLV% 56% [42-84]) and increase in Budd-Chiari syndrome (1891 cm3 [1601-2094], 121% [111-131]). Progression to high-grade encephalopathy was more common with smaller LV and PLV. A < 1000 cm3 threshold identified NA patients who later developed it with 93% (95%CI 83-98) specificity and odds ratio 10.6 (3.3-34.5) at median 5 days prior to onset, and risk of death in those with NA-drug-induced (DILI) or indeterminate disease with 91% (71-99) specificity and 63% (50-75) sensitivity. CONCLUSION: In patients with ALF/ALI, LV shows marked variation by the cause of disease, and in prognostic importance. In indeterminate and DILI cases, loss of volume to <1000 cm3 may indicate irreversible liver injury and regenerative failure and serve as an early clinical predictor for the development of high-grade encephalopathy and death.

Coil embolization for intrahepatic haemorrhage following liver biopsy in a patient with hepatitis C virus infection and hepatic microaneurysms.

Intrahepatic bleeding secondary to rupture of hepatic microaneurysms is an uncommon clinical entity more frequently associated with polyarteritis nodosa (PAN) or rarely with other vasculitis or autoimmune disease. Hepatic vasculitis is reported in chronic hepatitis C virus (HCV) infection and an association between hepatitis C and PAN is described. The current report presents the case of a middle-aged female patient with a medical history remarkable for HCV infection who underwent a percutaneous liver biopsy, which was complicated by severe intrahepatic and perihepatic haemorrhage. Computed tomography angiography revealed innumerous microaneurysms. She underwent transcatheter angiography and coil embolization of a peripheral branch of the right hepatic artery which controlled the bleeding. Subsequently, she was empirically treated with a course of Prednisolone. Follow-up imaging showed a good response to treatment.

Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience.

Primary Budd-Chiari syndrome is a rare cause of liver disease in children in the western world. Here we present a retrospective review of children with Primary Budd-Chiari syndrome presenting from January 2001 to November 2015 to our hospital. Seven children were identified. Their presentation was mostly chronic. All had predisposing factors for thrombosis and were started on anticoagulation. Radiological interventions (2 transjugular intrahepatic portosystemic shunts and 1 hepatic vein stenting), liver transplant and mesocaval shunt were done in 3, 2, and 1 patients, respectively; 1 child underwent bone marrow transplantation following transjugular intrahepatic portosystemic shunts and 1 child was managed only medically. After liver transplantation, one child died 3 years later as a result of subarachnoid haemorrhage, whereas others remain well at a median follow-up of 6 years. Despite high morbidity, the disease can have a good long-term outcome with a multidisciplinary approach.

Irreversible electroporation for the treatment of pancreatic neuroendocrine tumors.

BACKGROUNDS/AIMS: Resection or enucleation is currently the treatment of choice for small pancreatic neuroendocrine tumors (NETs). Irreversible electroporation is a novel ablative method that is used for locally advanced pancreatic adenocarcinoma, but little data exists for its use for pancreatic NETs. We report an early experience of IRE for early pancreatic NETs. METHODS: Between April 2014 and March 2015, 3 patients with small (<2 cm) pancreatic NETs were treated with percutaneous IRE. RESULTS: There were no adverse effects during the procedure. Mean hospital stay was 2.6 days. All patients remained disease free on 12-19 months follow up. One patient developed recurrent pancreatitis with pseudocyst formation. CONCLUSIONS: IRE for small tumors of the pancreas is practical and may offer advantages over other thermal ablative techniques, since it preserves vital structures such as blood vessels, bile and pancreatic ducts. Further data regarding the long term disease free interval is required to establish efficacy.

Liver resection for the treatment of a congenital intrahepatic portosystemic venous shunt.

Intrahepatic portosystemic shunts (IPSS) are rare congenital anomalies arising from disordered portal vein embryogenesis. It has been described in both children and adults and may be asymptomatic or be associated with a variety of neurophysiological and pulmonary complications. When recognized, early intervention to occlude the shunt will reverse the associated complications. Literature review reports of surgical and radiological occlusion of the shunt, but due to its rarity, a standard therapeutic protocol has not been established. A case of a 38-year-old woman with abdominal pain and low grade encephalopathy, diagnosed with an IPSS and treated by right hepatectomy was reported.

Congenital extrahepatic portosystemic shunt complicated by the development of hepatocellular carcinoma.

Congenital extrahepatic portosystemic shunt, also known as Abernethy malformation, is a rare congenital malformation. It causes shunting of blood through a communication between the portal and systemic veins such as a patent ductus venous. We report 3 cases of Abernethy malformation complicated by the development of hepatocellular carcinoma. Additionally, we comprehensively reviewed all previously reported cases and highlighted common features that may help in early diagnosis and appropriate management. Patients with Abernethy malformation may have an increased propensity to develop hepatocellular carcinoma. All 5 previously reported cases, plus the three of our patients, have a type 1 (complete) shunt suggesting a role for absent portal blood flow in the pathogenesis of hepatocellular carcinoma. Congenital extrahepatic portosystemic shunt should be sought for in cases with raised serum ammonia, hepatic encephalopathy or hepatocellular carcinoma in the absence of cirrhosis.

BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation.

DIAGNOSIS: It is recommended that the diagnosis of veno-occlusive disease (sinusoidal obstruction syndrome) [VOD (SOS)] be based primarily on established clinical criteria (modified Seattle or Baltimore criteria) (1A). Ultrasound imaging may be helpful in the exclusion of other disorders in patients with suspected VOD (SOS) (1C). It is recommended that liver biopsy be reserved for patients in whom the diagnosis of VOD (SOS) is unclear and there is a need to exclude other diagnoses (1C). It is recommended that liver biopsies are undertaken using the transjugular approach in order to reduce the risks associated with the procedure (1C). It is suggested that the role of plasminogen activator inhibitor 1 levels remains an area for further research but that these levels should not form part of the routine diagnostic work-up for VOD (SOS) at present (2C). RISK FACTORS: It is recommended that patients are assessed for risk factors for VOD (SOS) and that these risk factors are addressed prior to haematopoietic stem cell transplantation (1A). PROPHYLAXIS: Defibrotide is recommended at a dose of 6.25 mg/kg intravenously four times daily for the prevention of VOD (SOS) in children undergoing allogeneic stem cell transplantation with the following risk factors: pre-existing hepatic disease, second myeloablative transplant, allogeneic transplant for leukaemia beyond second relapse, conditioning with busulfan-containing regimens, prior treatment with gemtuzumab ozogamicin, diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis (1A). Defibrotide is suggested at a dose of 6.25 mg/kg intravenously four times daily for the prevention of VOD (SOS) in adults undergoing allogeneic stem cell transplantation with the following risk factors: pre-existing hepatic disease, second myeloablative transplant, allogeneic transplant for leukaemia beyond second relapse, conditioning with busulfan-containing regimens, prior treatment with gemtuzumab ozogamicin, diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis (2B). Prostaglandin E1 is not recommended in the prophylaxis of VOD (SOS) due to lack of efficacy and toxicity (1B). Pentoxifylline is not recommended in the prophylaxis of VOD (SOS) due to lack of efficacy (1A). Ursodeoxycholic acid is suggested for use in the prophylaxis of VOD (SOS) (2C). Heparin (unfractionated and low molecular weight) is not suggested for use in the prophylaxis of VOD (SOS) due to the risk of increased toxicity (2B). Antithrombin is not suggested for the prophylaxis of VOD (SOS) due to lack of efficacy (2B). TREATMENT: Defibrotide is recommended in the treatment of VOD (SOS) in adults and children (1B). Tissue plasminogen activator is not recommended for use in the treatment of VOD (SOS) due to the associated risk of haemorrhage (1B). N-acetylcysteine is not routinely recommended for use in the treatment of veno-occlusive disease due to lack of efficacy (1A). Methylprednisolone may be considered for use in the treatment of veno-occlusive disease with the appropriate caveats of caution regarding infection (2C). Judicious clinical care, particularly in the management of fluid balance, is recommended in the management of VOD (SOS) (1C). Early discussion with critical care specialists and a specialist hepatology unit is recommended in the management of VOD (SOS) and other treatment options including transjugular intrahepatic portosystemic shunt or hepatic transplantation may be considered (1C). SUMMARY: A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of veno-occlusive disease of the liver following haematopoietic stem cell transplantation (HSCT). This guideline includes recommendations for both prophylaxis and treatment of the condition and includes recommendations for children and adults undergoing HSCT.

Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update.

The British Society of Gastroenterology guidelines on the management of cholangiocarcinoma were originally published in 2002. This is the first update since then and is based on a comprehensive review of the recent literature, including data from randomised controlled trials, systematic reviews, meta-analyses, cohort, prospective and retrospective studies.

Mixed phenotype hepatocellular carcinoma after transarterial chemoembolization and liver transplantation.

We investigated the phenotype of hepatocellular carcinoma (HCC) in livers removed during transplantation after local ablation therapy by transarterial chemoembolization (TACE). This study involved 80 HCC nodules (40 treated with TACE and 40 not treated with local ablation before transplantation) observed in 64 explanted livers and included clinicopathological evaluations as well as single and double immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) for cytokeratin 19 (CK19), epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), and CD133. HCCs with complete necrosis post-TACE without viable tumors were excluded from the analysis. Cholangiolar, glandular, or spindle cell areas suggestive of a mixed hepatocholangiocellular phenotype were seen in 14 post-TACE HCCs and in none of the non-TACE HCCs (P < 0.001). According to single-epitope immunohistochemistry of post-TACE HCCs, CD133, CK19, EpCAM, and NCAM were expressed in 14 (35%), 8 (20%), 12 (30%), and 8 (20%), respectively. Only EpCAM was detected in 4 non-TACE HCC cases (10%). RT-PCR experiments using tissues obtained by laser microdissection showed that 4 of 5 investigated post-TACE HCCs expressed at least 1 of the markers, which were coexpressed in 3 of 5 tumors, whereas CD133 and EpCAM were individually expressed in 2 non-TACE HCCs. Double immunostaining showed that CD133(+) cells frequently coexpressed CK19, EpCAM, or NCAM. Interestingly, the recurrence rate for patients with CD133(+) post-TACE HCC was significantly higher than the rate for patients with CD133(-) post-TACE HCC (P = 0.025). In conclusion, HCC with the combined hepatocholangiocellular phenotype appears to be more frequent in post-TACE HCC versus untreated HCC. Further studies are needed to investigate the potential relationships between TACE and HCC subpopulations with a chemoembolization-resistant phenotype and their clinical significance.

Selective embolization for bleeding visceral artery pseudoaneurysms in patients with pancreatitis.

BACKGROUND: Pancreatitis is associated with arterial complications in 4%-10% of patients, with untreated mortality approaching 90%. Timely intervention at a specialist center can reduce the mortality to 15%. We present a single institution experience of selective embolization as first line management of bleeding pseudoaneurysms in pancreatitis. METHODS: Sixteen patients with pancreatitis and visceral artery pseudoaneurysms were identified from searches of the records of interventional angiography from January 2000 to June 2007. True visceral artery aneurysms and pseudoaneurysms arising as a result of post-operative pancreatic or biliary leak were excluded from the study. RESULTS: In 50% of the patients, bleeding complicated the initial presentation of pancreatitis. Alcohol was the offending agent in 10 patients, gallstones in 3, trauma, drug-induced and idiopathic pancreatitis in one each. All 16 patients had a contrast CT scan and 15 underwent coeliac axis angiography. The pseudoaneurysms ranging from 0.9 to 9.0 cm affected the splenic artery in 7 patients: hepatic in 3, gastroduodenal and right gastric in 2 each, and left gastric and pancreaticoduodenal in 1 each. One patient developed spontaneous thrombosis of the pseudoaneurysm. Fourteen patients had effective coil embolization of the pseudoaneurysm. One patient needed surgical exclusion of the pseudoaneurysm following difficulty in accessing the coeliac axis radiologically. There were no episodes of re-bleeding and no in-hospital mortality. CONCLUSIONS: Pseudoaneurysms are unrelated to the severity of pancreatitis and major hemorrhage can occur irrespective of their size. Co-existent portal hypertension and sepsis increase the risk of surgery. Angiography and selective coil embolization is a safe and effective way to arrest the hemorrhage.

Anaphylaxis from intravascular rupture of Hydatid disease following liver trauma.

Cystic Echinococcosis also known as cystic hydatid disease is a parasitic infection endemic in many parts of the world. Humans are accidental intermediate hosts with cysts most commonly developing in the liver. This case describes a rare presentation of hydatid disease following trauma to the liver. Intraparenchymal cyst rupture led to haemodynamic instability with release of the parasites protoscolices into hepatic venules producing severe life threatening anaphylaxis.

Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening.

UNLABELLED: Hepatocellular carcinoma (HCC) has traditionally been considered a rare complication of cirrhosis secondary to autoimmune hepatitis (AIH), yet the true incidence remains unknown due to a lack of published data. Consequently, some professional guidelines do not mandate routine surveillance for HCC in this condition. Our aims were to evaluate the rate at which HCC develops among a large, prospectively obtained cohort of patients with AIH at a single center. Demographic, clinical, and laboratory indices associated with the development of HCC were also identified. HCC was discovered in 15 of 243 patients with AIH, all of whom had type 1 AIH equating to 1090 cases per 100,000 patient follow-up years. HCC occurred in the same proportion of females as males, 6.1% versus 6.4%, P = 0.95. HCC occurred more frequently in patients who had cirrhosis at presentation, 9.3% versus 3.4%, P = 0.048, or who had a variceal bleed as the index presentation of AIH, 20% versus 5.3%, P = 0.003. The median duration from time of confirmed cirrhosis to a diagnosis of HCC was 102.5 months, range 12-195 months. Median survival in patients whose HCC was diagnosed on surveillance was 19 months (range 6-36 months) compared with 2 months (range 0-14 months) for patients presenting symptomatically (P = 0.042). CONCLUSION: Cirrhosis in AIH is the sine qua non for HCC development, which subsequently occurs at a rate of 1.1% per year and affects men and women in equal proportions.

Hepatic dysfunction in sickle cell disease: a new system of classification based on global assessment.

BACKGROUND & AIMS: Hepatic dysfunction in adults with sickle cell disease varies in character and severity from self-limited cholestasis to life-threatening acute liver failure and cirrhosis. Because previous attempts to describe patterns of liver disease have not reflected clinical experience, we aimed to characterize the presentation, clinicopathologic findings, and natural history of such patients. METHODS: We reviewed the clinical, laboratory, radiographic, and histologic features with the natural history of 38 patients (mean age, 33 years) with Hb SS, SC, or S-beta thalassemia referred to a tertiary liver center for assessment. RESULTS: Distinct disease patterns were identified that comprised massive hepatocellular necrosis (5%), acute severe sequestration and cholestasis in the context of sepsis (18%), cirrhosis (18%), chronic, fluctuating sequestration without cholestasis (21%), mechanical biliary obstruction (8%), siderosis without cirrhosis (8%), generalized cholangiopathy (8%), venous outflow obstruction (3%), and miscellaneous (11%). Of the 20 who required emergency admission, 8 did not survive their index admission, and 3 patients died during follow-up admissions (4 months-4 years later). There were 3 instances of hemorrhage related to liver biopsy. One patient underwent transplantation but died. Hematologic and biochemical markers did not discriminate well between survivors and nonsurvivors. The incidence of a second hepatic pathology (ie, viral hepatitis, autoimmune disease, transfusional siderosis) was 37% and was associated with the finding of more advanced histologic fibrosis. CONCLUSIONS: Patterns of hepatic dysfunction in sickle cell disease are diverse and demand clear characterization for each individual; however, groups with a poor prognosis can be identified after collation of clinical, laboratory, and radiologic data. Findings at biopsy (which is associated with higher risk of bleeding in this group) might be anticipated by noninvasive test results.

Traumatic pancreatic duct injury in children: minimally invasive approach to management.

BACKGROUND: The management of children with main pancreatic duct injuries is controversial. We report a series of patients with pancreatic trauma who were treated using minimally invasive techniques. METHODS: Retrospective review of children with pancreatic trauma treated at a UK tertiary referral institution between 1999 and 2004. RESULTS: Fifteen children (11 boys) were admitted with pancreatic trauma. Twelve (80%) were less than 50th centile for body weight. Contrast-enhanced computed tomography (CT) scans were used to define organ injury, supplemented by magnetic resonance cholangiopancreatography (MRCP) in 7. Twelve (80%) underwent diagnostic endoscopic retrograde cholangiopancreatography (ERCP) with a median time after injury of 11 (range, 6-29) days. The degree of pancreatic injury was defined by ERCP and CT/MRCP as grade II (n = 2), grade III (n = 4), grade IV (n = 9) (American Association for the Surgery of Trauma grades). Nine children had a transductal pancreatic stent inserted endoscopically. Computed tomography/ultrasound-guided drainage was performed in 4 children for acute fluid collections. Two children later underwent endoscopic cyst-gastrostomy, one of whom later required conversion to an open cyst-gastrostomy. CONCLUSION: Body habitus may predispose to pancreatic duct trauma. Contrast-enhanced CT scan (and MRCP) should dictate the need for ERCP. Transductal pancreatic stenting allows internal drainage of peripancreatic collections and may reestablish duct continuity, although a proportion still requires percutaneous or endoscopic cyst-gastrostomy drainage. Open surgery for pancreatic trauma should now be an exception.