Inflammatory hepatocellular adenoma, focal nodular hyperplasia and hepatic granulomas in one single patient : possible physiopathologic explanations.

We report the case of a hepatocellular adenoma associated with focal nodular hyperplasia and hepatic granulomas in a 30-yearsold woman. This association has rarely been described before but might be explained by underlying common pathophysiologic mechanisms. In this manuscript possible links between the three entities are discussed.

Mucin-producing hepatic cystic neoplasms: an uncommon but challenging disease often misdiagnosed and mismanaged.

Background: Mucin-producing hepatic cystic neoplasms (MHCN) are uncommon and potentially malignant.Methods: Nine MHCN were encountered in our centre for over 32 years. Patients' clinical, biological, radiological and pathological features were reviewed. Lesions were classified into Mucinous Cystic Neoplasms (MCN) and Intraductal Papillary Neoplasms of the Bile duct (IPNB) (WHO 2010 classification).Results: Five MCN and 4 IPNB were reviewed. Serum and intracystic tumour markers were insufficient to diagnose malignancy. Complications were encountered in five out of nine patients (56%), mean symptom duration was 26 months (range: 1-132). Three patients were mismanaged pre-referral. Radiological features enabled preoperative diagnosis in eight out of nine patients (89%). Greater tumour size, unilocular lesion and mural nodularity indicated malignancy. Radical tumour excision was achieved in eight patients. One IPNB patient was misdiagnosed and underwent unroofing. For 103 months median follow-up, five out of six patients with benign tumours were alive and disease-free, whereas the misdiagnosed IPNB recurred with fatal malignant transformation seven years later. Among the three patients with malignancies (median follow-up: 77 months), two IPNB died, one from cancer recurrence and one from unrelated causes, whereas the malignant MCN was alive and disease-free.Conclusions: Appropriate MHCN diagnosis is crucial, yet it is often misdiagnosed and mismanaged. The prognosis after complete excision is favourable.

Acute liver graft cellular rejection after interferon-free antiviral treatment for HCV infection. Is there a risk? A warning about three cases.

All patients transplanted for hepatitis C (HCV)- related cirrhosis will experience a recurrence of the viral disease on the liver graft with an accelerated course of the disease and a progression to advanced liver fibrosis in up to 50% of the patients at 5 years post-liver transplantation. HCV infection is a high risk for graft lost. We report here three cases of patients transplanted for hepatocellular carcinoma on HCV-related cirrhosis. All cases experienced an acute cellular rejection after the end of HCV therapy with direct acting antivirals (DAAs). We thus advocate for a close monitoring of tacrolimus and liver tests even a few months after the end of the treatment. Clinicians using DAAs after liver transplantation should be aware of the dynamics of tacrolimus levels during therapy and immunological changes that can occur even several weeks (or months) after the end of DAA treatment.

Impact of liver inflammation on whole body insulin resistance : a case report on primary biliary cholangitis.

Chronic liver diseases such as hepatitis C or non-alcoholic fatty liver disease could be associated with insulin resistance, even in the absence of cirrhosis or significant fibrosis. In this report, we present the case of a patient who was diagnosed with primary biliary cholangitis and metabolic syndrome. Initial evaluation also revealed diabetes with elevated fasting plasma glucose and glycated hemoglobin. After eight weeks of treatment with ursodeoxycholic acid, a complete normalization of the hepatic biological tests was observed. A few months later, while body weight and abdominal perimeter remained stable, fasting blood glucose and glycated hemoglobin decreased significantly, compatible with diabetes disappearance. This finding supports the concept that the inflamed liver plays a major role in the pathogenesis of insulin resistance and diabetes occurrence in chronic liver diseases, including primary biliary cholangitis.

The role of the pathologist and clinical implications in colorectal liver metastasis.

Colorectal liver metastases (CRLM) affect about 50% of colorectal cancer patients. With the improvement of neoadjuvant chemotherapy and the introduction of targeted therapy, resectability of CRLM and survival rates have improved over time. However, 60-70% of patients still recur. Several pathological and molecular parameters have been described as prognostic factors after CRLM resection. These parameters encompass not only tumoral features, but also non-tumoral ones, such as chemotherapy related liver injury, or factors related to tumour environment, namely Immunoscore. This review summarizes these prognostic indicators to clarify which patho-molecular parameters should be addressed in the pathological report.

The Belgian Association for Study of the Liver Guidance Document on the Management of Adult and Paediatric Non-Alcoholic Fatty Liver Disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) is highly prevalent and associated with considerable liver-related and non-liverrelated morbidity and mortality. There is, however, a lot of uncertainty on how to handle NAFLD in clinical practice. The current guidance document, compiled under the aegis of the Belgian Association for the Study of the Liver by a panel of experts in NAFLD, from a broad range of different specialties, covers many questions encountered in daily clinical practice regarding diagnosis, screening, therapy and follow-up in adult and paediatric patients. Guidance statements in this document are based on the available evidence whenever possible. In case of absence of evidence or inconsistency of the data, guidance statements were formulated based on consensus of the expert panel. This guidance document is intended as a help for clinicians (general practitioners and all involved specialties) to implement the most recent evidence and insights in the field of NAFLD within a Belgian perspective.

Cholestatic hepatitis after diagnostic ajmaline challenge.

We report a cholestatic hepatitis in an elderly woman after ajmaline challenge during electrophysiological testing for Brugada syndrome. No other medication was reported in the previous 6 months of the onset of jaundice. Liver biopsy showed a cholestatic hepatitis with mild biliary damage. Liver enzymes normalized within 2 weeks as well as jaundice. To the best of our knowledge this is the second case of histologically proved cholestatic hepatitis induced by intravenous ajmaline testing.

Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients.

AIM: To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients. BACKGROUND: Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the role of HLA-DRB1 genotype has not been evaluated, though it's associated with fibrosis in autoimmune hepatitis. PATIENTS AND METHODS: This observational study, included 89 stable LT recipient transplanted between 2004-2012 with mean follow-up of 4.3years, 281 serial PBs (3.1 biopsy/child) and human leukocyte antigen (HLA) antibody data. PBs were taken 1-2, 2-3, 3-5, 5-7, and 7-10years post-LT, and evaluated for inflammation and fibrosis using liver allograft fibrosis score (LAFSc). The evolution of fibrosis, inflammation and related predisposing factors were analysed. FINDINGS: HLA-DRB1*03/04 allele and Class II DSA were significantly associated with portal fibrosis (p=0.03; p=0.03, respectively). Portal inflammation was predisposed by Class II DSA (p=0.02) and non-HLA antibody presence (p=0.01). Non-portal fibrosis wasn't predisposed by inflammation. Lobular inflammation was associated with non-HLA antibodies. INTERPRETATION: We conclusively demonstrated that allograft inflammation results in fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies. The HLA-DRB1*03/04 allele caused genetic predisposition for fibrosis. FUNDING: None.

Septuagenarian and octogenarian donors provide excellent liver grafts for transplantation.

BACKGROUND: Wider utilization of liver grafts from donors ≥ 70 years old could substantially expand the organ pool, but their use remains limited by fear of poorer outcomes. We examined the results at our center of liver transplantation (OLT) using livers from donors ≥ 70 years old. METHODS: From February 2003 to August 2010, we performed 450 OLT including 58 (13%) using donors ≥ 70 whose outcomes were compared with those using donors <70 years old. RESULTS: Cerebrovascular causes of death predominated among donors ≥ 70 (85% vs 47% in donors <70; P < .001). In contrast, traumatic causes of death predominated among donors <70 (36% vs 14% in donors ≥ 70; P = .002). Unlike grafts from donors <70 years old, grafts from older individuals had no additional risk factors (steatosis, high sodium, or hemodynamic instability). Both groups were comparable for cold and warm ischemia times. No difference was noted in posttransplant peak transaminases, incidence of primary nonfunction, hepatic artery thrombosis, biliary strictures, or retransplantation rates between groups. The 1- and 5-year patient survivals were 88% and 82% in recipients of livers <70 versus 90% and 84% in those from ≥ 70 years old (P = .705). Recipients of older grafts, who were 6 years older than recipients of younger grafts (P < .001), tended to have a lower laboratory Model for End-Stage Liver Disease score (P = .074). CONCLUSIONS: Short and mid-term survival following OLT using donors ≥ 70 yo can be excellent provided that there is adequate donor and recipient selection. Septuagenarians and octogenarians with cerebrovascular ischemic and bleeding accidents represent a large pool of potential donors whose wider use could substantially reduce mortality on the OLT waiting list.

Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension.

BACKGROUND: Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection. AIM: To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome. METHODS: All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case­control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed. RESULTS: On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3­2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1­19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2­22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003). CONCLUSIONS: HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation

Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study.

BACKGROUND: Idiopathic noncirrhotic portal hypertension (INCPH) is a rare disease in the Western world. As a result, little is known about the clinical characteristics and outcome of these patients. Survival in these patients is considered to be similar to that of the general population. AIM: To investigate the clinical manifestations, pathophysiology, outcome and determinants of survival in Western INCPH patients. METHODS: Multicentre cohort study of INCPH patients. RESULTS: A total of 62 patients were followed for a median time of 90 months (range 24-310). Initial manifestations leading to the diagnosis of INCPH were related to portal hypertension in 82% of the patients. Histological signs of portal blood supply disturbances were present in nearly all patients. During follow-up, 12 of 62 patients developed liver decompensation, of which four were considered for liver transplantation. One patient died in the context of variceal bleeding. Hepatocellular carcinoma was not observed during follow-up. A total of 23 patients died during follow-up, only four of them due to liver related mortality. The Kaplan-Meier estimates for overall survival were 100% (95% CI 95-100%), 78% (95% CI 67-89%) and 56% (95% CI 40-72%) at 1, 5 and 10 years respectively. Survival for INCPH was significantly decreased (P < 0.001) compared to survival of the general population. Ascites was an independent predictor of poor outcome. CONCLUSIONS: In comparison to the general population, survival in INCPH patients is poor. Mortality is related to associated disorders and medical conditions occurring at older age. Patients rarely die due to liver related complications. Patients with ascites have a poor prognosis.

Attempt to rescue discarded human liver grafts by end ischemic hypothermic oxygenated machine perfusion.

In a porcine liver transplant model, a brief period of oxygenated hypothermic machine perfusion (HMP) at the end of simple cold storage (SCS) has been shown to improve the viability of damaged liver grafts. To test the clinical validity of this strategy, we randomized SCS-discarded human liver grafts to either 4 hours of HMP (n = 13) or an additional 4 hours of SCS (n = 14). All livers were then warm reperfused to mimic ischemia-reperfusion injury ex vivo. The settings for HMP were: portal vein: 3 mm Hg, 300 mL/min and hepatic artery: 20 mm Hg, pO(2): 300 mm Hg. Perfusion used Kidney Machine Perfusion Solution at 4°C to 8°C. During warm reperfusion, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) values were higher (P < .015) among the SCS versus HMP methods at all times. The AST slope was lower in HMP versus SCS (P = .01). The LDH slope tended to be lower for HMP versus SCS (P = .07). Morphological scores were not different between HMP and SCS. At the start of warm reperfusion, MAPK was lower in HMP versus SCS (P = .02). Endothelin-1 (EDN1) and ICAM-1 tended to be lower in HMP versus SCS (P = .1 and .07, respectively). No difference was noted in MAPK, EDN1, and ICAM-1 after 60 or 120 minutes of warm reperfusion. In conclusion, HMP down-regulated MAPK and tended to reduce EDN1 and ICAM-1 mRNA in human liver grafts. During warm reperfusion, HMP versus SCS livers showed reduced AST and LDH release but no morphological difference. Further optimization of liver HMP may require different timing/duration of perfusion and/or an higher perfusion temperature.

Can apparent diffusion coefficient discriminate ischemic from nonischemic livers? A pilot experimental study.

PURPOSE: Using magnetic resonance imaging, the apparent diffusion coefficient (ADC) is an indicator to assess cerebral ischemia. The aim of this porcine study was to evaluate whether ADC assessed hepatic ischemia during ex vivo hypothermic machine perfusion (HMP) as well as in vivo. METHODS: Ex vivo: ADC of normal versus warm ischemic (WI) livers was assessed during HMP and subsequent rewarming to mimic ischemia-reperfusion injury. As the preservation solution, we used either an acellular solution or diluted blood. WI was induced in the left lobe or in the whole liver and compared 2-hour WI and non-WI. In vivo: One liver was scanned with the left lobe vessels occluded for 2-hour WI and subsequently for 3 hour reperfusion to compare with the right lobe without WI. Aspartate aminotransferase (AST) in the perfusate and morphology were used as surrogates of WI. RESULTS: In all WI livers, AST reached high levels and histology showed severe injury. Ex vivo ADC during acellular perfusion showed negligible differences between the livers with versus without WI, namely, 0.75 x 10(-3) or 0.88 x 10(-3) mm(2)/s during HMP. Ex vivo ADC using sanguineous perfusion showed 1.11 x 10(-3) or 0.83 x 10(-3) mm(2)/s during HMP in regions with versus without WI, respectively, a difference that remained stable during the whole experiment. ADC in vivo decreased from the physiological level of 1.07 x 10(-3) mm(2)/s to 0.75 x 10(-3) mm(2)/s in the first 30 minutes of WI, whereas ADC in the non-WI liver remained constant. CONCLUSION: ADC in vivo decreased during hepatic ischemia, as previously seen in cerebral ischemia. However, the effect of WI on ADC was less clear during ex vivo HMP.

Influence of flow and addition of oxygen during porcine liver hypothermic machine perfusion.

INTRODUCTION: In contrast with kidneys, data on hypothermic machine perfusion (HMP) of livers remain scarce. Optimal liver HMP is poorly defined. Superiority of liver HMP over simple cold storage (SCS), the current standard preservation, must be proven before HMP is applied clinically. In this study, morphology and adenosine triphosphate (ATP) contents of HMP livers at different flows and with versus without O(2) studied in a porcine ex vivo model were compared to SCS. METHODS: Pig livers were procured, flushed with HTK and preserved via SCS or HMP at 3 HMP settings: high flow (HF); low flow (LF); low flow + O(2) (300 mm Hg) (LFO). HMP livers were perfused via the hepatic artery (HA) and portal vein (PV) with KPS-1 TM at 4 degrees C to 6 degrees C for 24 hours with HF: PV: 3 to 5 mm Hg, 1 mL/g liver/min for HA and 25 mm Hg; LF: PV: 3 to 5 mm Hg, 0.5 ml/g liver/min with HA: 20 mm Hg. Morphology and ATP levels were measured in preserved liver tissues. RESULTS: Throughout the SCS preservation, livers remained intact. In HMP livers, vacuoles appeared after 4 hours of preservation in the HF group and after 12 hours in the LF livers. LFO livers remained intact with limited vacuoles. Compared to SCS, HMP livers showed dilated sinusoids, particularly in the HF group. ATP remained relatively constant or even increased during HMP, particularly in the LF group, whereas ATP decreased after SCS. CONCLUSION: Among the various HMP settings, HMP with LFO was superior. ATP levels were the highest in LF. In contrast with all HMP groups, SCS showed the lowest ATP levels, indicating that HMP has the potential to better preserve energy stores.

Unusual accumulation of glycogen in liver parenchymal cells in a patient with anorexia nervosa.

Anorexia nervosa is an eating disorder characterized by a fear of weight gain and a preoccupation with body image. Although hepatic involvement has been reported in patients with anorexia nervosa, the mechanism is not fully understood. We describe a patient with anorexia nervosa with liver function abnormalities. Light and electron microscopic observations revealed a remarkable accumulation of glycogen in hepatocytes. These results suggest that adaptive responses to starvation may alter carbohydrate metabolism in patients with anorexia nervosa.