Natasha Chandok

Pain Management in the Cirrhotic Patient: The Clinical Challenge

Pain management in patients with cirrhosis is a difficult clinical challenge for health care professionals, and few prospective studies have offered an evidence-based approach. In patients with end-stage liver disease, adverse events from analgesics are frequent, potentially fatal, and often avoidable. Severe complications from analgesia in these patients include hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, which can result in substantial morbidity and even death. In general, acetaminophen at reduced dosing is a safe option. In patients with cirrhosis, nonsteroidal anti-inflammatory drugs should be avoided to avert renal failure, and opiates should be avoided or used sparingly, with low and infrequent dosing, to prevent encephalopathy. For this review, we searched the available literature using PubMed and MEDLINE with no limits.

Burden of de novo malignancy in the liver transplant recipient

Recipients of liver transplantation (LT) have a higher overall risk (2‐3 times on average) of developing de novo malignancies than the general population, with standardized incidence ratios ranging from 1.0 for breast and prostate cancers to 3‐4 for colon cancer and up to 12 for esophageal and oropharyngeal cancers. Aside from immunosuppression, other identified risk factors for de novo malignancies include the patients age, a history of alcoholic liver disease or primary sclerosing cholangitis, smoking, and viral infections with oncogenic potential. Despite outcome studies showing that de novo malignancies are major causes of mortality and morbidity after LT, there are no guidelines for cancer surveillance protocols or immunosuppression protocols to lower the incidence of de novo cancers. Patient education, particularly for smoking cessation and excess sun avoidance, and regular clinical follow‐up remain the standard of care. Further research in epidemiology, risk factors, and the effectiveness of screening and management protocols is needed to develop evidence‐based guidelines for the prevention and treatment of de novo malignancies. Liver Transpl, 2012.

Representing complexity well: a story about teamwork, with implications for how we teach collaboration

Medical Education 2012: 46: 869–877

Increased risk of severe recurrence of hepatitis C virus in liver transplant recipients of donation after cardiac death allografts.

Background. In hepatitis C virus (HCV) recipients of donation after cardiac death (DCD) grafts, there is suggestion of lower rates of graft survival, indicating that DCD grafts themselves may represent a significant risk factor for severe recurrence of HCV. Methods. We evaluated all DCD liver transplant recipients from August 2006 to February 2011 at our center. Recipients with HCV who received a DCD graft (group 1, HCV+ DCD, n=17) were compared with non-HCV recipients transplanted with a DCD graft (group 2, HCV− DCD, n=15), and with a matched group of HCV recipients transplanted with a donation after brain death (DBD) graft (group 3, HCV+ DBD, n=42). Results. A trend of poorer graft survival was seen in HCV+ patients who underwent a DCD transplant (group 1) compared with HCV− patients who underwent a DCD transplant (group 2) (P=0.14). Importantly, a statistically significant difference in graft survival was seen in HCV+ patients undergoing DCD transplant (group 1) (73%) as compared with DBD transplant (group 3) (93%)(P=0.01). There was a statistically significant increase in HCV recurrence at 3 months (76% vs. 16%) (P=0.005) and severe HCV recurrence within the first year (47% vs. 10%) in the DCD group (P=0.004). Conclusions. HCV recurrence is more severe and progresses more rapidly in HCV+ recipients who receive grafts from DCD compared with those who receive grafts from DBD. DCD liver transplantation in HCV+ recipients is associated with a higher rate of graft failure compared with those who receive grafts from DBD. Caution must be taken when using DCD grafts in HCV+ recipients.

Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts

The impact of ischemia/reperfusion injury in the setting of transplantation for hepatocellular carcinoma (HCC) has not been thoroughly investigated. The present study examined data from the Scientific Registry of Transplant Recipients for all recipients of deceased donor liver transplants performed between January 1, 1995 and October 31, 2011. In a multivariate Cox analysis, significant predictors of patient survival included the following: HCC diagnosis (P < 0.01), donation after cardiac death (DCD) allograft (P < 0.001), hepatitis C virus‐positive status (P < 0.01), recipient age (P < 0.01), donor age (P < 0.001), Model for End‐Stage Liver Disease score (P < 0.001), recipient race, and an alpha‐fetoprotein level > 400 ng/mL at the time of transplantation. In order to test whether the decreased survival seen for HCC recipients of DCD grafts was more than would be expected because of the inferior nature of DCD grafts and the diagnosis of HCC, a DCD allograft/HCC diagnosis interaction term was created to look for potentiation of effect. In a multivariate analysis adjusted for all other covariates, this interaction term was statistically significant (P = 0.049) and confirmed that there was potentiation of inferior survival with the use of DCD allografts in recipients with HCC. In conclusion, patient survival and graft survival were inferior for HCC recipients of DCD allografts versus recipients of donation after brain death allografts. This potentiation of effect of inferior survival remained even after adjustments for the inherent inferiority observed in DCD allografts as well as other known risk factors. It is hypothesized that this difference could reflect an increased rate of recurrence of HCC. Liver Transpl 19:1214–1223, 2013.

Inhibition of Cdc25A suppresses hepato-renal cystogenesis in rodent models of polycystic kidney and liver disease

BACKGROUND & AIMS In polycystic kidney disease and polycystic liver disease (PLD), the normally nonproliferative hepato-renal epithelia acquire a proliferative, cystic phenotype that is linked to overexpression of cell division cycle 25 (Cdc25)A phosphatase and cell-cycle deregulation. We investigated the effects of Cdc25A inhibition in mice and rats via genetic and pharmacologic approaches. METHODS Cdc25A(+/-) mice (which have reduced levels of Cdc25A) were cross-bred with polycystic kidney and hepatic disease 1 (Pkhd1(del2/del2)) mice (which have increased levels of Cdc25A and develop hepatic cysts). Cdc25A expression was analyzed in livers of control and polycystic kidney (PCK) rats, control and polycystic kidney 2 (Pkd2(ws25/-)) mice, healthy individuals, and patients with PLD. We examined effects of pharmacologic inhibition of Cdc25A with vitamin K3 (VK3) on the cell cycle, proliferation, and cyst expansion in vitro; hepato-renal cystogenesis in PCK rats and Pkd2(ws25/-)mice; and expression of Cdc25A and the cell-cycle proteins regulated by Cdc25A. We also examined the effects of the Cdc25A inhibitor PM-20 on hepato-renal cystogenesis in Pkd2(ws25/-) mice. RESULTS Liver weights and hepatic and fibrotic areas were decreased by 32%-52% in Cdc25A(+/-):Pkhd1(del2/del2) mice, compared with Pkhd1(del2/del2) mice. VK3 altered the cell cycle and reduced proliferation of cultured cholangiocytes by 32%-83% and decreased growth of cultured cysts by 23%-67%. In PCK rats and Pkd2(ws25/-) mice, VK3 reduced liver and kidney weights and hepato-renal cystic and fibrotic areas by 18%-34%. PM-20 decreased hepato-renal cystogenesis in Pkd2(ws25/-) mice by 15%. CONCLUSIONS Cdc25A inhibitors block cell-cycle progression and proliferation, reduce liver and kidney weights and cyst growth in animal models of polycystic kidney disease and PLD, and might be developed as therapeutics for these diseases.

Should a Lower Quality Organ Go to the Least Sick Patient? Model for End-Stage Liver Disease Score and Donor Risk Index as Predictors of Early Allograft Dysfunction

BACKGROUND There is a global tendency to justify transplanting extended criteria organs (ECD; Donor Risk Index [DRI] ≥ 1.7) into recipients with a lower Model for End-Stage Liver Disease (MELD) score and to transplant standard criteria organs (DRI < 1.7) into recipients with a higher MELD scores. There is a lack of evidence in the current literature to justify this assumption. METHODS A review of our prospectively entered database for donation after brain death (DBD) liver transplantation (n = 310) between January 1, 2006, and September 30, 2010, was performed. DRI was dichotomized as <1.7 and ≥ 1.7. Recipients were divided into 3 strata, those with high (≥ 27), moderate (15-26), and low MELD (<15) scores. The recently validated definition of early allograft dysfunction (EAD) was used. We analyzed EAD and its relation with donor DRI and recipient MELD scores. RESULTS The overall incidence of EAD was 24.5%. Mortality in the first 6 months in recipients with EAD was 20% compared with 3.4% for those without EAD (relative risk [RR], 5.56, 95% confidence interval [CI], 1.96-15.73; P < .001). Graft failure rate in the first 6 months in those with EAD was 27% compared with 5.8% for those without EAD (RR, 4.63; 95% CI, 2.02-10.6; P < .001). In patients with low MELD scores, a significantly increased rate of EAD (25%) was seen in patients transplanted with a high DRI liver compared with those transplanted with a low DRI liver (6.25%; P = .012). In moderate and high MELD recipients, there was no significant difference in the rate of EAD in patients transplanted with a high DRI liver (62%) compared with those transplanted with a low DRI liver (59%). CONCLUSION These results suggest that contrary to common belief it is not justified to preferentially allocate organs with higher DRI to recipients with lower MELD scores.

Early Allograft Dysfunction Is Associated With Excess Resource Utilization After Liver Transplantation

BACKGROUND There are limited data on length of stay (LOS) following liver transplantation (LT), yet this is an important health services metric that directly correlates with early post-LT health care costs. The primary objective of this study was to examine the relationship between early allograft dysfunction (EAD) and LOS after LT. The secondary objective was to identify additional recipient, donor, and operative factors associated with LOS. METHODS Adult patients undergoing primary LT over a 32-month period were prospectively examined at a single center. Subjects fulfilling standard criteria for EAD were compared with those not meeting the definition. Variables associated with increased LOS on ordinal logistic regression were identified. RESULTS Subjects with EAD had longer mean hospital LOS than those without (42.5 ± 38.9 days vs 27.4 ± 31 days; P = .003). Subjects with EAD also had longer mean intensive care LOS (8.61 ± 10.28 days vs 5.45 ± 11.6 days; P = .048). Additional factors significantly associated with LOS included Model for End-Stage Liver Disease (MELD) score, recipient location before LT, and postoperative surgical complications. CONCLUSIONS EAD is associated with longer hospitalization after LT. MELD score, preoperative recipient location, and postoperative complications were significantly associated with LOS. From a cost-containment perspective, these findings have implications on resource allocation.

A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma.

AIM To compare the clinical outcome and pathologic features of non-alcoholic steatohepatitis (NASH) patients with hepatocellular carcinoma (HCC) and hepatitic C virus (HCV) patients with HCC (another group in which HCC is commonly seen) undergoing liver transplantation. METHODS Patients transplanted for HCV and NASH at our institution from January 2000 to April 2011 were analyzed. All explanted liver histology and pre-transplant liver biopsies were examined by two specialist liver histopathologists. Patient demographics, disease free survival, explant liver characteristics and HCC features (tumour number, cumulative tumour size, vascular invasion and differentiation) were compared between HCV and NASH liver transplant recipients. RESULTS A total of 102 patients with NASH and 283 patients with HCV were transplanted. The incidence of HCC in NASH transplant recipients was 16.7% (17/102). The incidence of HCC in HCV transplant recipients was 22.6% (64/283). Patients with NASH-HCC were statistically older than HCV-HCC patients (P < 0.001). A significantly higher proportion of HCV-HCC patients had vascular invasion (23.4% vs 6.4%, P = 0.002) and poorly differentiated HCC (4.7% vs 0%, P < 0.001) compared to the NASH-HCC group. A trend of poorer recurrence free survival at 5 years was seen in HCV-HCC patients compared to NASH-HCC who underwent a Liver transplantation (P = 0.11). CONCLUSION Patients transplanted for NASH-HCC appear to have less aggressive tumour features compared to those with HCV-HCC, which likely in part accounts for their improved recurrence free survival.

Management of primary sclerosing cholangitis: Conventions and controversies

Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy that results in fibrotic strictures and dilations of the intra- and extrahepatic bile ducts. PSC is uncommon, occurs predominantly in males and has a strong association with inflammatory bowel disease. While the pathogenesis of PSC has not been fully elucidated, emerging evidence supports roles for the innate and adaptive immune systems, and genome-wide analyses have identified several genetic associations. Using the best available evidence, the present review summarizes the current understanding of the diagnosis, pathogenesis and management of PSC. Despite its rarity, there is an urgent need for collaborative research efforts to advance therapeutic options for PSC beyond liver transplantation.