M. Isabel Fiel

Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus.

De novo autoimmune hepatitis has been described in both pediatric and adult liver transplantation (LT) recipients. Studies of small numbers of patients have proposed it to be an alloimmune hepatitis or form of chronic rejection. We have recently noted an increasing number of patients with post‐LT recurrent hepatitis C virus (HCV) developing this, with an apparent negative impact on outcome and survival. We term this entity posttransplant plasma cell hepatitis (PCH). A search of our institutions pathology database was performed with the terms “plasma cell(s),” “lymphoplasmacytic infiltrate,” and “liver allograft.” A histological scoring system was devised to more reliably diagnose PCH in the setting of recurrent HCV. Thirty‐eight patients were identified, and their clinical data were analyzed. Sixty percent had a negative outcome as defined by the development of cirrhosis, need for retransplantation, or death. Eighty‐two percent had recent lowering of immunosuppression or subtherapeutic calcineurin inhibitor levels; 58% developed PCH within 2 years post‐LT. Histologic resolution of PCH was associated with good outcome (P < 0.001). Patients not receiving treatment had a negative outcome (P = 0.007) as did patients receiving corticosteroids as therapy (P = 0.02). Persistence (P = 0.007) or recurrence of PCH was associated with negative outcome. In conclusion, PCH is a histologic variant of rejection. On liver biopsy, PCH can at times be difficult to diagnose, and the use of a standardized scoring system is recommended to differentiate it from other forms of allograft dysfunction. Treatment by optimization of immunosuppression without the use of corticosteroids appears effective. The development of PCH in the setting of recurrent HCV is a negative prognostic factor for patient outcome and allograft failure. Liver Transpl 14:861–871, 2008.

LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA: EXTENSION OF INDICATIONS BASED ON MOLECULAR MARKERS

BACKGROUND/AIMSnLiver transplantation usually cures hepatocellular carcinoma when the Milan selection criteria are applied, whereas there is substantial risk of posttransplant recurrence with tumors beyond these criteria. This study uses molecular data to identify a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have favorable outcomes.nnnMETHODSnAllelic imbalance of 18 microsatellites was analyzed in 70 consecutive patients (35 within Milan, 35 beyond Milan criteria) transplanted for hepatocellular carcinoma of whom 24 had recurrence and 46 survived at least 5 years recurrence-free. Fractional allelic imbalance (the fraction of significant microsatellites that demonstrated allelic imbalance) and relevant clinical/pathological variables were tested for correlation with time to recurrence.nnnRESULTSnAllelic imbalance in 9/18 microsatellites correlated with recurrence. Fractional allelic imbalance > 0.27 and macrovascular invasion were independent predictors of recurrence in patients with tumors beyond Milan criteria; the probability of recurrence at 5 years was 85% with fractional allelic imbalance > or = 0.27 vs. 10% when < 0.27 (p=0.0002). An algorithm including Milan criteria and fractional allelic imbalance status is 89% accurate in predicting tumor recurrence after transplantation.nnnCONCLUSIONnAnalysis of allelic imbalance of 9 microsatellites identifies a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have a low risk of posttransplant recurrence.

Recurrent hepatitis C after retransplantation: Factors affecting graft and patient outcome†

Retransplantation (re‐LT) of patients with recurrent hepatitis C virus (HCV) carries significant morbidity and mortality, negatively impacting on an already scarce donor allograft pool. In this study, we investigated the outcome of allografts and patients after re‐LT due to recurrent HCV. Between 1989 and 2002, 47 patients were retransplanted at our institution due to HCV‐related graft failure. Clinical HCV recurrence after re‐LT was diagnosed when patients had acute liver enzyme elevation correlated with histological recurrence. The independent influence of these variables on survival was tested using Cox regression model. Chi‐squared tests were used to examine the influence of individual demographic and pre/perioperative variables on recurrence. Thirty‐one (66%) patients died after re‐LT (median 2.2 months). Donor age >60, clinical HCV recurrence, and graft failure due to cirrhosis were significant risk factors for mortality (risk ratios of 3.6, 3.3, and 2.4, respectively). Pre‐LT MELD score was lower among survivors (22± 5 vs. 27± 8). Following re‐LT, 38 patients had at least one biopsy due to acute liver dysfunction; 19 of them (50%) had recurrence within the first 3 months. High‐dose solumedrol was correlated with early recurrence. No association was found between time of recurrence after the first LT and time of recurrence after re‐LT. In conclusion, patients with cirrhosis due to recurrent HCV undergoing re‐LT have an extremely high mortality rate; older allografts should be avoided in retransplanting these patients. The timing of clinical recurrence after initial liver transplantation is not predictive of the timing of recurrence after re‐LT. Patients experiencing early graft failure due to accelerated forms of HCV should not be denied re‐LT with the expectation that a similar disease course will occur after re‐LT. (Liver Transpl 2005;11:1567–1573.)

Plasma cell hepatitis in hepatitis C virus patients post–liver transplantation: Case‐control study showing poor outcome and predictive features in the liver explant

Plasma cell hepatitis (PCH) is characterized by plasma cell infiltration seen in allografts of patients who underwent liver transplantation (LT) for conditions other than autoimmune hepatitis. We identified 40 PCH patients who underwent LT for hepatitis C virus (HCV) by searching our pathology database (1994–2006) for the keywords liver allograft, lymphoplasmacytic, and plasma cell(s). We selected 2 control patients who received LT for HCV for each PCH case. The control patients were matched according to date of LT and availability of biopsy material at the time interval to development of PCH in PCH patients. Explant and post‐LT biopsy slides were blindly reviewed by 2 liver pathologists and the severity of the plasma cell infiltrate was scored. A score of 3 (plasma cells composing >30% of the infiltrate) defined PCH in allograft biopsies. Five random areas of dense inflammation were also examined in explant livers and the highest score was used. Poor outcome was defined as death or advanced fibrosis (stage ≥ 4 of 6). We found that PCH patients were more likely to have worse outcomes than control patients (65% versus 40%, P < 0.01), including increased mortality (50% versus 30%, P < 0.05). Kaplan‐Meier survival analysis showed significantly worse survival for PCH patients from 4 to 10 years post‐LT (P < 0.05). Explants from 40% of PCH patients had a score of 3 compared to 18% of control patients (P < 0.01). We found that the development of PCH is associated with poor outcome in patients undergoing LT for HCV. The association of significant plasma cell infiltrates in native livers of HCV patients developing PCH suggests that some patients may have a predisposition to developing PCH. Liver Transpl 15:1826–1833, 2009.

Fractional allelic imbalance could allow for the development of an equitable transplant selection policy for patients with hepatocellular carcinoma

Liver transplantation (LT) in the presence of hepatocellular carcinoma (HCC) remains a controversial issue because the current staging systems are not sufficiently predictive of outcomes. Paraffin blocks from 183 patients that underwent LT in the presence of HCC were collected. Molecular analysis was carried out blindly on the native liver specimens in all cases with respect to recurrence outcomes. The fractional allelic imbalance (FAI) rate index was determined in each case and was used to compare the acquired mutational load between different tumors. The FAI was determined from the microdissected tissue site displaying the greatest amount of acquired allelic loss. FAI was found to be the strongest predictor of recurrence followed by vascular invasion and then by tumor number or hepatic lobar involvement. Based on these findings, 3 prognostic models were constructed for selection of candidates for LT in patients with concomitant HCC. Molecular markers of tumor progression are the strongest predictors of HCC recurrence currently available, surpassing all components of the tumor‐node‐metastasis classification system for staging of malignant tumors (TNM), including vascular invasion. Incorporation of these molecular markers of tumor progression could help resolve the ongoing conundrum of organ allocation for patients with HCC. Liver Transpl 2007.

Rapid regression of atherosclerosis with MTP inhibitor treatment

OBJECTIVEnRegression of atherosclerosis is a vital treatment goal of atherosclerotic vascular disease. Inhibitors of the microsomal triglyceride transfer protein (MTP) have been shown to reduce apolipoprotein B (apoB)-containing lipoproteins in animals and humans effectively. Therefore, the major aim of our study is to evaluate the effect of MTP inhibition on atherosclerotic plaque regression.nnnMETHODSnLDL-receptor-deficient (LDLr(-/-)) mice were fed a Western diet for 16 weeks and then harvested for baseline (nxa0=xa08), switched to chow diet (nxa0=xa08) or chow diet containing MTP inhibitor (BMS 212122; nxa0=xa08) for 2 weeks before harvesting.nnnRESULTSnTreatment with MTP inhibitor led to rapid reduction in plasma lipid levels, which were accompanied by a significant decrease in lipid content and monocyte-derived (CD68+) cells in atherosclerotic plaques compared to baseline and chow diet control groups. MTP inhibitor-treated mice had increased collagen content, a marker associated with increased stability in human plaques. Furthermore, plaques of these mice showed a significant decrease in tissue factor and pro-inflammatory M1 macrophage marker monocyte chemoattractant protein-1 (MCP-I) and an increase in anti-inflammatory M2 macrophage markers arginase-I and mannose receptor 1 compared to mice in the baseline group.nnnCONCLUSIONnReversal of hyperlipidemia in atherosclerotic mice by inhibition of MTP leads to rapid and beneficial changes in the composition and inflammatory state of the plaque.

Recurrent hepatic sarcoidosis post‐liver transplantation manifesting with severe hypercalcemia: A case report and review of the literature

Sarcoidosis is a systemic granulomatous disease primarily involving the lungs, lymph nodes, skin, eyes and nervous system; liver involvement is asymptomatic in most cases. However, once the patient develops clinical symptoms liver disease is usually progressive and may necessitate orthotopic liver transplantation. There are a few reports of asymptomatic recurrent sarcoidosis developing within the liver allograft. We report a case of early recurrence of sarcoidosis in the liver allograft diagnosed on biopsy in a patient who presented with severe hypercalcemia, kidney dysfunction, and increase in size of abdominal lymph nodes. The liver chemistry tests were within normal limits. The patient responded well to steroid treatment by normalizing serum calcium and creatinine levels and reducing lymph node size. To date, there has been no report in the literature of symptomatic recurrence of hepatic sarcoidosis following orthotopic liver transplantation. (Liver Transpl 2005;11:1611–1614.)

Rapid Reversal of Parenteral-Nutrition-Associated Cirrhosis Following Isolated Intestinal Transplantation

IntroductionLiver disease and the development of hepatic fibrosis are complications associated with total parenteral nutrition (TPN). Patients developing cirrhosis and portal hypertension in the setting of intestinal failure have a high mortality and may require combined liver and intestinal transplantation which carries much higher morbidity and mortality than isolated intestinal transplantation.DiscussionRecently, regression of hepatic fibrosis in patients with TPN liver disease has been described following intestinal transplantation. To date, there has been no demonstration of the reversal of established cirrhosis due to long-term TPN injury. Herein, we describe a patient with intestinal failure who developed cirrhosis from long-standing TPN injury and underwent isolated intestinal transplantation. He had no overt clinical stigmata of portal hypertension and had preserved liver function. Serial liver biopsies were reviewed and assessed with standard histology and quantitation of fibrosis using image analysis. Dramatic regression of fibrosis and reversal of cirrhosis were observed 17xa0months posttransplantation. Image analysis demonstrated a 14% total decrease in the percentage area of fibrosis.ConclusionsCirrhosis related to TPN may be rapidly reversible after isolated intestinal transplantation. Such patients may be able to undergo isolated intestinal transplantation if they do not have hepatic synthetic compromise or clinical stigmata of portal hypertension.

The development of hepatoportal sclerosis and portal hypertension due to didanosine use in HIV

Hepatoportal sclerosis (HPS) is one of several entities known to cause noncirrhotic portal hypertension. To date, its etiology is unknown. There have been increasing reports of HPS occurring in patients with human immunodeficiency virus (HIV), and the US Food and Drug Administration (FDA) recently issued an advisory regarding the development of noncirrhotic portal hypertension in association with didanosine (ddI) use. We report on a patient with HIV who had taken ddI for 4xa0years and who developed portal hypertension. Histopathological review of paired liver biopsies showed an initial drug hepatotoxicity, microvascular liver injury, and the presence of HPS. Despite cessation of ddI, the latter biopsy showed resolution of the drug-induced injury, but it also showed progression of the HPS. The patient’s portal hypertension also progressed suggestive of an unremitting vascular injury. This case demonstrates the development of HPS resulting from a drug-induced microvascular injury. The paired biopsies demonstrate that the initial vascular injury may disappear but that the portal hypertension and HPS progress.

Increasing hepatic arteriole wall thickness and decreased luminal diameter occur with increasing age in normal livers

BACKGROUND & AIMSnThere is no data to suggest that the size of bile ducts, portal venules, and hepatic arterioles varies according to age in the normal human liver. We sought to examine whether hepatic arteriolar size, wall thickness, and luminal diameter change with increasing age.nnnMETHODSnHistologically normal liver specimens from 90 live and deceased donors were separated into three groups of thirty: donor age<30, 31-60, and>60years old. Trichrome-stained slides were de-identified and assessed by a liver pathologist blinded to donor age. Morphometric measurements were taken of the hepatic arteriole, the cross-sectional diameter, and its wall thickness. The arteriole was measured at its widest diameter, the arteriolar wall at its thickest portion, and the luminal diameter between its widest points.nnnRESULTSnThere was no difference in number of arterioles or bile ducts or in arteriolar cross-sectional diameter among the groups and no correlation with age was found. An increasing arteriolar wall thickness and a decrease in luminal diameter with advancing age were noted; no difference in bile duct size among the groups was found. There was a significant difference in wall thickness/total cross-sectional diameter with extremes in age (21-30 age group vs. 71-80 age group, p=0.0009) with an accompanying significant decrease in luminal diameter/cross-sectional diameter between the same groups (p=0.00002).nnnCONCLUSIONSnIncreasing hepatic arteriolar wall thickness and decreased arteriolar cross-sectional diameter occur with increasing age in the normal human liver.