Giorgio Enrico Gerunda

Hepatocyte transplantation as a treatment for glycogen storage disease type 1a

Treatment of many inherited disorders of hepatic metabolism is still challenging. Hepatocyte transplantation was done in a 47-year-old woman who had glycogen storage disease type 1a and severe fasting hypoglycaemia. 2 billion viable hepatocytes were infused via an indwelling portal-vein catheter, followed by a triple immunosuppression regimen with mycophenolate mofetil, tacrolimus, and steroids. 9 months after transplantation, on only tacrolimus, she eats a normal diet and can fast for 7 h without experiencing hypoglycaemia. Our results show that hepatocyte transplantation might be an alternative to liver transplantation in glycogen storage disease type 1a.

Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients

BACKGROUND/AIMS The electroencephalogram (EEG) is frequently altered in cirrhotic patients. We, therefore, performed a study to ascertain the features and the prognosis of cirrhotic patients without current overt hepatic encephalopathy (OHE) who have EEG alterations. METHODS A series of 296 consecutive cirrhotic patients who had undergone quantified-EEG was studied. The median follow-up was 442 days, 128 patients had bouts of OHE and 78 patients died from liver-related causes. Another group of 124 cirrhotic patients with a median follow-up of 223 days was examined to validate the prognostic model. RESULTS EEG alterations were detected in 38% of the patients. The prevalence of EEG alterations was associated with the severity of cirrhosis (class B: odds ratio (OR) = 2.3, 95% confidence interval (CI) = 1.2-4.7; class C: OR = 3.5, 95% CI = 1.6-7.7), but not with the aetiology (alcoholic vs. non-alcoholic: OR = 0.9; 95% CI = 0.5-1.5). The EEG predicted the occurrence of OHE (chi2 = 26; P < 0.001) and mortality (chi2 = 34; P < 0.001), also adjusting for Child-Pugh class by a multivariate analysis. In the patients with a Child-Pugh score of > or = 8, the EEG discriminated between those patients with a higher 1-year risk of OHE (hazard ratio (HR) = 3.3, 95% CI = 1.8-6.1) and death (HR = 3.1, 95% CI = 1.7-5.6). CONCLUSIONS In conclusion, quantified-EEG had a prognostic value for the occurrence of bouts of OHE and mortality in cirrhotic patients.

Performance of tests for latent tuberculosis in different groups of immunocompromised patients.

BACKGROUND Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their management is hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-gamma release blood assays T-SPOT.TB (TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy for latent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown. METHODS AND RESULTS Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneously performed, their results were compared, and intertest agreement was evaluated. Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p < 0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (kappa = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (kappa = 0.16) or QFT-IT (kappa = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001). CONCLUSIONS Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based on these results, we recommend tailoring application of the new blood IFN-gamma assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

The impact of liver disease and medical complications on quality of life and psychological distress before and after liver transplantation.

BACKGROUND/AIM The impact of liver disease and medical complications on quality of life (QOL) and psychological distress before and after orthotopic liver transplantation (OLT) is a matter of growing interest. METHODS Perceived QOL (LEIPAD Quality of Life test) and psychological distress (Brief Symptom Inventory, BSI) were assessed in 40 cirrhotic patients listed for OLT (Group A) and in 101 liver transplant recipients (Groups B to G=0-6, 7-12, 13-24, 25-36, 37-48, 49-60 months post-OLT). Patients were also evaluated for medical complications, blood levels of immunosuppressive agents and recurrence of liver disease. RESULTS QOL and psychological distress were significantly better in most of the post-OLT groups than in cirrhotic patients. Among post-OLT patients, a significantly worse QOL was perceived at 13-24 months (Life Satisfaction: Group D vs G, p=0.024; Cognitive Functioning: Group D vs F, p=0.024), while significantly greater psychological distress was detected at 7-12 months (Anxiety and Interpersonal Sensitivity: Group C vs Group B, p=0.032 and p=0.023, respectively). Medical complications and immunosuppressive therapy did not influence QOL or psychological distress after OLT. Within 6 months after OLT, patients with HCV recurrence showed significantly greater Depression (p=0.023), Anxiety (p=0.038), Phobic Anxiety (p=0.001), and Paranoid Ideation (p=0.033) than anti-HCV negative patients. CONCLUSIONS Liver transplantation improves psychological distress and most, but not all, QOL domains. Recurrent HCV infection is associated with greater psychological distress.

Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial.

Bleeding is a feared complication of invasive procedures in patients with cirrhosis and significant coagulopathy (as defined by routine coagulation tests) and is used to justify preprocedure use of fresh frozen plasma (FFP) and/or platelets (PLT). Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet count), and its use may avoid unnecessary blood product transfusion in patients with cirrhosis and significant coagulopathy (defined in this study as INR >1.8 and/or platelet count <50 × 109/L) who will be undergoing an invasive procedure. Sixty patients were randomly allocated to TEG‐guided transfusion strategy or standard of care (SOC; 1:1 TEG:SOC). The TEG group would receive FFP if the reaction time (r) was >40 min and/or PLT if maximum amplitude (MA) was <30 mm. All SOC patients received FFP and/or PLT per hospital guidelines. Endpoints were blood product use and bleeding complications. Baseline characteristics of the two groups were similar. Per protocol, all subjects in the SOC group received blood product transfusions versus 5 in the TEG group (100% vs. 16.7%; P < 0.0001). Sixteen SOC (53.3%) received FFP, 10 (33.3%) PLT, and 4 (13.3%) both FFP and PLT. In the TEG group, none received FFP alone (P < 0.0001 vs. SOC), 2 received PLT (6.7%; P = 0.009 vs. SOC), and 3 both FFP and PLT (not significant). Postprocedure bleeding occurred in only 1 patient (SOC group) after large‐volume paracentesis. Conclusions: In patients with cirrhosis and significant coagulopathy before invasive procedures, TEG‐guided transfusion strategy leads to a significantly lower use of blood products compared to SOC (transfusion guided by INR and platelet count), without an increase in bleeding complications. Remarkably, even in patients with significant coagulopathy, postprocedure bleeding was rare, indicating that TEG thresholds should be reevaluated. (Hepatology 2016;63:566–573)

Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal Function

We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA‐based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy‐eight patients were randomized (Evr n = 52; CsA n = 26). The 1‐year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥3 (estimated glomerular filtration rate <60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.

HHV-6A in Syncytial Giant-Cell Hepatitis

Syncytial giant-cell hepatitis is a rare but severe form of hepatitis that is associated with autoimmune diseases, drug reactions, and viral infections. We used serologic, molecular, and immunohistochemical methods to search for an infectious cause in a case of syncytial giant-cell hepatitis that developed in a liver-transplant recipient who had latent infection with variant B of human herpesvirus 6 (HHV-6B) and who had received the organ from a donor with variant A latent infection (HHV-6A). At the onset of the disease, the detection of HHV-6A (but not HHV-6B) DNA in plasma, in affected liver tissue, and in single micromanipulated syncytial giant cells with the use of two different polymerase-chain-reaction (PCR) assays indicated the presence of active HHV-6A infection in the patient. Expression of the HHV-6A-specific early protein, p41/38, but not of the HHV-6B-specific late protein, p101, was demonstrated only in liver syncytial giant cells in the absence of other infectious pathogens. The same markers of HHV-6A active infection were documented in serial follow-up samples from the patient and disappeared only at the resolution of syncytial giant-cell hepatitis. Neither HHV-6B DNA nor late protein was identified in the same follow-up samples from the patient. Thus, HHV-6A may be a cause of syncytial giant-cell hepatitis.

Pancreatic metastases from renal cell carcinoma：The state of the art

Pancreatic metastases are rare, with a reported incidence varying from 1.6% to 11% in autopsy studies of patients with advanced malignancy. In clinical series, the frequency of pancreatic metastases ranges from 2% to 5% of all pancreatic malignant tumors. However, the pancreas is an elective site for metastases from carcinoma of the kidney and this peculiarity has been reported by several studies. The epidemiology, clinical presentation, and treatment of pancreatic metastases from renal cell carcinoma are known from single-institution case reports and literature reviews. There is currently very limited experience with the surgical resection of isolated pancreatic metastasis, and the role of surgery in the management of these patients has not been clearly defined. In fact, for many years pancreatic resections were associated with high rates of morbidity and mortality, and metastatic disease to the pancreas was considered to be a terminal-stage condition. More recently, a significant reduction in the operative risk following major pancreatic surgery has been demonstrated, thus extending the indication for these operations to patients with metastatic disease.

Balancing Donor and Recipient Risk Factors in Liver Transplantation: The Value of D‐MELD With Particular Reference to HCV Recipients

Donor–recipient match is a matter of debate in liver transplantation. D‐MELD (donor age × recipient biochemical model for end‐stage liver disease [MELD]) and other factors were analyzed on a national Italian database recording 5946 liver transplants. Primary endpoint was to determine factors predictive of 3‐year patient survival. D‐MELD cutoff predictive of 5‐year patient survival <50% (5yrsPS<50%) was investigated. A prognosis calculator was implemented (http://www.D‐MELD.com). Differences among D‐MELD deciles allowed their regrouping into three D‐MELD classes (A < 338, B 338–1628, C >1628). At 3 years, the odds ratio (OR) for death was 2.03 (95% confidence interval [CI], 1.44–2.85) in D‐MELD class C versus B. The OR was 0.40 (95% CI, 0.24–0.66) in class A versus class B. Other predictors were hepatitis C virus (HCV; OR = 1.42; 95% CI, 1.11–1.81), hepatitis B virus (HBV; OR = 0.69; 95% CI, 0.51–0.93), retransplant (OR = 1.82; 95% CI, 1.16–2.87) and low‐volume center (OR = 1.48; 95% CI, 1.11–1.99). Cox regressions up to 90 months confirmed results. The hazard ratio was 1.97 (95% CI, 1.59–2.43) for D‐MELD class C versus class B and 0.42 (95% CI, 0.29–0.60) for D‐MELD class A versus class B. Recipient age, HCV, HBV and retransplant were also significant. The 5yrsPS<50% cutoff was identified only in HCV patients (D‐MELD ≥ 1750). The innovative approach offered by D‐MELD and covariates is helpful in predicting outcome after liver transplantation, especially in HCV recipients.

Long-Term Persistence of Low Bone Density in Orthotopic Liver Transplantation

Abstract: We determined bone density and metabolism in 46 patients (35 males, 11 females) who had undergone liver transplantation 1–48 months previously. Twenty-one patients were then followed for the next 24 months. At each visit, blood and urine samples for bone and liver metabolism parameters, as well as spinal and femoral dual-energy X-ray absorptiometry (DXA) scans, were obtained. Basal spinal and femoral density was low (p<0.001). Patients with pre-transplant cholestatic diseases had lower spinal density than all the other subjects (p<0.05) and the cumulative methylprednisolone intake was an independent negative predictor of total hip density (p<0.02). At baseline, urinary hydroxyproline and N-telopeptide were at the upper normal level and decreased only after 24 months of follow-up (p<0.05). During the first year of follow-up, femoral density decreased (p<0.05) and a partial recovery was observed for both spine and femur after 24 months. After 12 months, femoral bone density was negatively associated with serum cyclosporin A levels (p<0.005) and cumulative methylprednisolone intake (p<0.05), while the percent decrease in spinal density after the first 12 months was negatively predicted by mean daily methylprednisolone intake (p<0.05). In patients with pre-transplant cholestatic diseases, femoral and spinal density increased after the first (p<0.05) and second year (p<0.05), respectively. In patients with previous post-necrotic cirrhosis, femoral density decreased after 12 months (p<0.05) and was still lower than baseline after 24 months (p<0.05). However, at the end of the study the cumulative percentage of femoral neck osteoporosis was 43%. In conclusion, an elevated prevalence of spinal and femoral osteoporosis is present even many years after liver transplantation, with immunosuppressive treatment and pre-transplant liver disease being the most important pathogenetic factors.