Carmen M. Stanca

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.

Chronic ductopenic rejection in patients with recurrent hepatitis C virus treated with pegylated interferon alfa-2a and ribavirin

Background. Interferon use for post liver transplantation (LT) recurrent hepatitis C (HCV) has not consistently been associated with acute cellular rejection (ACR). We examined the incidence of chronic ductopenic rejection (CR) in patients receiving pegylated interferon alfa-2a and ribavirin (PEG) to treat recurrent HCV. Methods. A chart review of 12 patients developing CR while receiving an escalating dose regimen of PEG with protocol liver biopsies every 6 months was conducted. Values are shown as median (range). Results. Twelve of the 70 patients treated with PEG developed CR. Median age at LT was 53 (37–63) years; immunosuppression consisted of tacrolimus or cyclosporine with prednisone. PEG was started at 3.6 (0.2–13.5) years after LT. Two patients had one episode of ACR before PEG. Four patients had first ACR while receiving PEG. CR was diagnosed after 12 (4–17) months of PEG; by then 8 patients had undetectable HCV-RNA. Tacrolimus and cyclosporine levels (ng/mL) were 7.9 (3.2–18.9) and 76 (71–93) before PEG, and 6.9 (3.7–9.7) and 130 (81–153) at CR. Six patients were treated more than 1 year with PEG; three had undetectable HCV-RNA when CR was diagnosed. Five patients are being treated for CR; one has been listed for LT; two patients were retransplanted. Five patients died as a result of sepsis partially related to CR. Conclusions. Treatment with pegylated-interferon alpha-2a and ribavirin may trigger rapidly progressive CR in patients with therapeutic immunosuppressive trough levels, with or without first inducing ACR.

Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver.

Glycyrrhizin (GL) is used in Japan for the treatment of chronic hepatitis C. Following intravenous administration, GL is eliminated mainly by excretion into bile. Hepatocyte uptake of GL is a carrier-mediated process with characteristics resembling the organic anion transporting polypeptides (OATPs, solute carrier gene family SLC21A). We, therefore, studied whether GL is a potential transport substrate of the OATPs of rat and human liver. Because transport of GL could not be measured directly, GL-mediated cis-inhibition of [3H]estrone-3-sulfate or [35S]bromosulfophthalein uptake was analyzed kinetically in Xenopus laevis oocytes injected with cRNA coding for OATPs. GL inhibited [3H]estrone-3-sulfate uptake by 75-100% in oocytes expressing rat Oatp4, human OATP-C or human OATP8, members of the OATP1B subfamily that are expressed predominantly in hepatocytes. Dixon plots indicated a non-competitive type of inhibition, with Ki values of 6.1, 15.9 and 12.5 μmol/l, respectively. In contrast, GL inhibition of rat Oatp1, Oatp2 and Oatp3 and human OATP-A and OATP-B was only between 0 and 53%. In conclusion, GL is an inhibitor and, therefore, potentially a transport substrate of the liver-specific OATPs in rat and man. The rate at which GL is taken up into the liver may depend upon the function and expression levels of these hepatocellular OATPs.

Intranasal Desmopressin Versus Blood Transfusion in Cirrhotic Patients With Coagulopathy Undergoing Dental Extraction: A Randomized Controlled Trial

PURPOSE Cirrhotic patients waiting for liver transplantation who need dental extractions are given fresh frozen plasma and/or platelets to correct coagulopathy. This is costly and may be associated with transfusion reactions and fluid overload. We evaluated the efficacy of intranasal desmopressin as an alternative to transfusion to correct the coagulopathy of cirrhotic patients undergoing dental extraction. PATIENTS AND METHODS Cirrhotic patients with platelet counts of 30,000 to 50,000/microL and/or international normalized ratio (INR) 2.0 to 3.0 were enrolled in a prospective, controlled, randomized clinical trial. Blood transfusion (fresh frozen plasma 10 mL/kg and/or 1 unit of single donor platelets, respectively) or intranasal desmopressin (300 microg) were given before dental extraction. A standard oral and maxillofacial surgical treatment protocol was performed by the same surgeon. Patients were followed for postextraction bleeding and side-effects over the next 24 to 48 hours. RESULTS No significant differences were noted between the 2 groups in gender, age, INR, platelet count, creatinine, total bilirubin, ALT, albumin, MELD score, or number of teeth removed (median 3 vs 4). The number of teeth removed ranged between 1 and 31 in the desmopressin group and 1 and 22 in the transfusion group. No patients in desmopressin group required rescue blood transfusion after extraction. One patient in the transfusion group had bleeding after the procedure and required an additional transfusion. Another patient experienced an allergic reaction at the end of transfusion, which was effectively treated with diphenhydramine. Treatment associated average costs were lower for desmopressin (

Evaluation of fatigue in U.S. patients with primary biliary cirrhosis

700/patient) compared with transfusion (

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

1,173/patient). CONCLUSIONS Intranasal desmopressin was as effective as blood transfusion in achieving hemostasis in cirrhotic patients with moderate coagulopathy undergoing dental extraction. Intranasal desmopressin was much more convenient, less expensive, and well tolerated.

Exacerbation of sickle cell disease itself as a cause of abnormal liver chemistry tests.

OBJECTIVES:Fatigue, which may have a significant impact on quality of life, is the most common reported symptom in primary biliary cirrhosis (PBC). Multiple instruments to quantify fatigue and quality of life in liver disease have been validated, but have not been broadly applied to U.S. PBC patients. This study examines the extent of fatigue and its effect on quality of life in U.S. PBC patients.METHODS:Seventy patients with PBC were administered two validated questionnaires about quality of life (the Mayo version of the NIDDK-QA) and fatigue (the Fisk Fatigue Impact Score) and a proposed physical measure of fatigue in PBC (the grip strength test) on the day of routine physician visit. Nonparametric methods were employed.RESULTS:The fatigue and quality of life domain scores (physical functioning, liver symptoms, health satisfaction, Karnofsky index) discriminated between patients with and without self-reported fatigue (p < 0.05), as opposed to the grip strength results. Fatigue and quality of life domains correlated strongly with each other (r between 0.33 and 0.74, p ≤ 0.006) and not with the grip strength results. Neither quality of life nor fatigue scores correlated with age.CONCLUSIONS:The correlation between fatigue and quality of life scores suggests fatigue has an impact on quality of life in U.S. primary biliary cirrhosis patients. However, our fatigue scores suggest U.S. PBC patients have less fatigue than non-U.S. PBC patients. The grip strength is an insensitive measure of fatigue in U.S. PBC patients.

The Dynamic and Clinical Significance of Autoantibodies and Immunoglobulins in Liver Transplant Recipients

Aim:  This long‐term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT).

Transplantation Trends in Primary Biliary Cirrhosis

Liver pathology occurring in patients with sickle cell disease is commonly related to viral hepatitis or hepatic iron deposition due to repeated transfusions; cholestasis and cirrhosis may also occur. Consequently, the differential diagnosis of abnormal liver tests in patients with sickle cell anemia is often complicated. We report the case of a patient presenting with jaundice and abnormal liver biochemistries, without typical evidence of the liver diseases associated with sickle cell anemia. Biochemical markers for viral hepatitis were negative. CT scan only showed hepatomegaly. The liver biopsy revealed marked sinusoidal congestion with red blood cells without significant steatosis or increased iron deposition. The patients medical history corroborated with biochemical tests and histological examination of the liver suggested that worsening hemolysis related to increased sickling of erythrocytes intrahepatically led to sinusoidal dilatation and probably caused the abnormal liver tests.

Natural history of small duct primary sclerosing cholangitis: a case series with review of the literature

Little is known about autoantibody pattern in liver transplantation (LT). The aim of the study was to examine autoantibodies (AAB) and immunoglobulins in patients with end‐stage liver disease before and after LT. Patients with LT who underwent post‐LT biopsies between 10/2008 and 8/2011 were enrolled. AAB were assessed at the time of LT and liver biopsy. Demographics, serum immunoglobulins, AAB, and liver histology (explant, post‐LT biopsies) were analyzed. Two hundred and twenty patients (M/F 143/77; age at LT 54 (19–73)) were included; AAB and immunoglobulins were evaluated in 76 patients. Length of follow‐up from LT was 285 (30–1462) days. Sixty‐one percent of patients had hepatitis C (HCV); 83% developed recurrent HCV. A significant decrease in IgG, IgA, IgM (p < 0.001 each), anticardiolipin antibodies IgG and IgM (p = 0.02), and beta‐2 microglobulin (p = 0.004) was observed post‐LT. HCV patients had higher IgG (p = 0.005), rheumatoid factor (p = 0.044) before LT; elevated IgM was associated with increased inflammation in the explant (p = 0.007). Lower IgG levels and antismooth muscle antibodies were present before LT in a higher percentage in patients who would develop recurrent HCV (p = 0.004, p = 0.077, respectively). In conclusion, AAB change significantly after LT and have a different pattern in HCV. Some immunological markers are associated with HCV recurrence and advanced inflammation on explant.