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This chapter addresses the unique aspects of hepatic physiology and liver diseases in older adults. Aging is associated with reduced metabolic and regenerative capacity of the liver, and the clinical presentation and prognosis of many liver disorders can be different in older adults compared with younger persons. In particular, drug-induced liver injury and acute liver failure have a worse prognosis in the elderly. Older patients often have endured decades of the metabolic syndrome, and nonalcoholic steatohepatitis-related cirrhosis is increasingly observed with advancing age. Because longer duration of cirrhosis is associated with a greater risk of hepatocellular carcinoma, this tumor and other malignancies of the biliary tract are more common in elderly patients. Liver transplantation should be considered in selected older candidates guided by their physiologic status rather than by their chronologic age.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death.386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure.Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death.A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

The management of autoimmune and cholestatic liver disorders is a challenging area of hepatology. Autoimmune and cholestatic liver diseases represent a comparatively small proportion of hepatobiliary disorders, yet their appropriate management is of critical importance for patient survival. In this article, management strategies are discussed, including the indications and expectations of pharmacologic therapy, endoscopic approaches, and the role of liver transplantation.

Coagulopathy is an essential component of the acute liver failure (ALF) syndrome and reflects the central role of liver function in hemostasis. ALF is a syndrome characterized by the development of hepatic encephalopathy and coagulopathy within 24 weeks of the onset of acute liver disease. Coagulopathy in this setting is a useful prognostic tool in ALF and a dynamic indicator of the hepatic function. If severe, it can be associated with bleeding and is commonly a major obstacle to the performance of invasive procedures in patients with ALF. This review focuses on the epidemiology, pathophysiology, presentation, evaluation, and management of coagulopathy in ALF.

Primary biliary cirrhosis (PBC) is an uncommon chronic cholestatic liver disease that primarily afflicts young and middle-aged Caucasian women; there are limited data on the clinical presentation and disease severity among non-Caucasian patients with this disease. The goal of this study was to examine differences in the severity of liver disease between Caucasian and non-Caucasian patients with PBC screened for enrollment in a large national multicenter clinical trial. Demographic features, symptoms, physical findings, and laboratory tests obtained during screening were examined in 535 patients with PBC with respect to ethnicity, gender, and antimitochondrial antibody (AMA) status; 73 of 535 (13.6%) were non-Caucasian (21 were African American, and 42 were Hispanic). Non-Caucasians were more likely than Caucasians to be ineligible for participation in the clinical trial (46.5% versus 25.1%, P = 0.0001), primarily because of greater disease severity. African Americans and Hispanics were also more likely to have a lower activity level, more severe pruritus, and more advanced disease. However, the mean age, male-to-female ratio, and seroprevalence of AMA positivity were similar between the 2 groups. Conclusion: Liver disease severity at clinical presentation is higher among non-Caucasians than Caucasians with PBC, and this cannot be explained by demographic or serologic features alone. Possible mechanisms underlying this health discrepancy are not clear, but increased awareness of PBC as a cause of chronic cholestatic liver disease is critical in evaluating non-Caucasian patients in the United States. (HEPATOLOGY 2007.)

1. Livers from donors previously exposed to hepatitis B virus (HBV) can fail after transplantation as a result of severe HBV reactivation in the transplant recipient. 2. Antibody against hepatitis B core antigen (HBcAb) in the donor is a marker for risk for transmission of HBV and reactivation after liver transplantation. 3. Recipient HBcAb positivity and antibody to hepatitis B surface antigen (HBsAb) positivity are associated with less risk for HBV reactivation. Conversely, the absence of HBcAb and/or HBsAb in the transplant recipient, higher Child-Pugh score, and presence of HBV DNA in the donor liver may be risk factors for HBV reactivation in the transplant recipient. 4. Recipients of HBcAb-positive (HBcAb(+)) livers at high risk for HBV reactivation should be treated prophylactically with lamivudine alone or a combination of hepatitis B immunoglobulin (HBIg) and lamivudine. The value of monoprophylaxis with HBIg has not been established in this setting. 5. Until data from larger studies are available, for low-risk recipients of HBcAb(+) livers, no prophylaxis, with very close serological and virological monitoring, appears to be a potential alternative to lamivudine monoprophylaxis. 6. Recipients of HBcAb-negative livers should be investigated for HBV infection when an episode of allograft dysfunction is not readily explained by the usual causes (rejection, ischemia, or hepatitis C recurrence).

Coagulopathy in patients with liver disease results from impairments in the clotting and fibrinolytic systems, as well as from reduced number and function of platelets. Parenteral vitamin K replacement corrects coagulopathy related to biliary obstruction, bacterial overgrowth, or malnutrition. Vitamin K is less effective for coagulopathy caused by severe parenchymal liver injury. Transfusion of fresh frozen plasma is the hallmark of treatment of significant coagulopathy in patients with liver disease and active bleeding. Transfusion of fresh frozen plasma also reverses moderate to severe coagulopathy of cirrhosis prior to invasive procedures. Cryoprecipitate is useful for severe coagulopathy with hypofibrinogenemia, especially when avoidance of volume overload is desired. Exchange plasmapheresis is useful in selected patients with coagulopathy due to liver disease, in whom fresh frozen plasma fails to correct coagulopathy or in patients who have coexistent severe fluid overload. Platelet transfusions, pooled or single donor, are useful in thrombocytopenic patients prior to performing invasive procedures or in the presence of significant bleeding, especially when the platelet count is below 50,000/mL. The use of recombinant factor VIIa and thrombopoietin therapy for correction of coagulopathy and thrombocytopenia, respectively, in patients with cirrhosis, is currently under investigation. Therapy with prothrombin complex concentrates, 1-deamino-8-D-arginine vasopressin and antithrombin III concentrates for the management of coagulopathy caused by liver disease can be hazardous and the use of these products is considered investigational at the present time.

We have shown that IgA-class antimitochondrial autoantibodies (AMA) can be detected in the bile and saliva of patients with PBC, suggesting that AMA are secreted into the luminal fluid across bile ducts and salivary glands. These data prompted us to determine whether AMA of the IgA isotype may be transported across other epithelial mucosa. Therefore, we tested for the presence of AMA in the urine specimens of 83 patients with PBC and 58 non-PBC controls including healthy individuals and patients with other liver diseases. Patients enrolled in this study had no history of renal disease, and we confirmed there was less than 50 microgram/mL of protein in each of the urine specimens. Interestingly, we found that AMA were present in the urine of 71/83 (86%) of all patients with PBC and in 71/78 (91%) of patients with PBC that were serum AMA positive. In contrast, AMA were not detected in any of the 58 control urine specimens. Of particular interest, AMA of the IgA isotype was present in 57/83 (69%) of patients with PBC, and in 52 of these 57, we found secretory-type IgA. In a nested random subgroup of urine samples, the prevalence of the IgA2 AMA was 6/18 (33%), significantly lower than in matched serum samples, 13/16 (81%, P =.007). These data show that AMA of the IgA isotype is secreted into urine from the uroepithelium of patients with PBC, and support the thesis that PBC originated from either a mucosal challenge or a loss of mucosal tolerance.

Solid-organ transplantation has emerged as one of the most significant medical advances in the management of end-stage organ disease to date. However, a long term successful outcome after transplantation relies heavily upon the extended, if not lifelong, intake of immunosuppressive medication. Noncompliance with the medication regimen may have devastating effects on the graft and the patient. Furthermore, the effects of noncompliance place an additional burden on the medical resources available and the already scarce organ supply. The magnitude of post-transplant noncompliance and factors associated with noncompliance with various immunosuppressant drugs are reviewed. Patient, physician, social and family relationships interact in a complex manner in the post-transplant scenario and problems here could underlie noncompliance. The paper also includes a review of the methods of evaluating and monitoring noncompliance. Preventive and remedial measures that may help the transplant team to effectively manage this problem are suggested. The multidisciplinary nature of post-transplant patient management and the need for a cohesive approach toward the patient is emphasised. With the identification of patients at higher risk for noncompliance, close monitoring and early intervention, it may be possible to effectively control the effects of noncompliance until newer strategies are developed which permit immunosuppression-free transplantation.

The mechanisms by which hepatitis C virus (HCV) induces chronic infection in the vast majority of infected individuals are unknown. Sequences within the HCV E1 and E2 envelope genes were analyzed during the acute phase of hepatitis C in 12 patients with different clinical outcomes. Acute resolving hepatitis was associated with relative evolutionary stasis of the heterogeneous viral population (quasispecies), whereas progressing hepatitis correlated with genetic evolution of HCV. Consistent with the hypothesis of selective pressure by the host immune system, the sequence changes occurred almost exclusively within the hypervariable region 1 of the E2 gene and were temporally correlated with antibody seroconversion. These data indicate that the evolutionary dynamics of the HCV quasispecies during the acute phase of hepatitis C predict whether the infection will resolve or become chronic.

Clinical prediction of portopulmonary hypertension(PPHTN) is critical in the preoperative evaluation of candidates for orthotopic liver transplantation (OLT) because of its association with significant morbidity and mortality. To determine the clinical, laboratory, and echocardiographic predictors of PPHTN, we retrospectively evaluated 55 candidates before OLT From those, 8 candidates had pulmonary hypertension ([HTN] group A) and 47 candidates did not (group B). Pulmonary HTN was defined as a mean pulmonary artery pressure (PAP) of 25 mm Hg or greater and either elevated pulmonary vascular resistance or normal pulmonary artery wedge pressure. The significant predictors of PPHTN were (1) systemic arterial HTN (63% in group A v 9% in group B; P < .001), (2) loud pulmonary component of the second heart sound (38% v 2%; P = .001), (3) right ventricular (RV) heave (38% v 4%; P = .002), (4) RV dilatation by echocardiogram (63% v 0%; P < .001), (5) RV hypertrophy by echocardiogram (38% v 0%; P = .001), and (6) echocardiogram-estimated systolic PAP (SPAP) greater than 40 mm Hg (63% v 2%; P < .001). The sensitivity of these variables for the detection of pulmonary HTN ranges from 37% to 63%, and their specificity from 91% to 100%. We conclude that several clinical and echocardiographic features are significantly associated with pulmonary HTN in patients with cirrhosis. In particular, echocardiogram-estimated SPAP greater than 40 mm Hg is strongly associated with pulmonary HTN and is specific. These predictors, however, are not sensitive enough to identify all the patients with PPHTN. Therefore, the evaluation of a combination of these variables may be useful for the preoperative identification of pulmonary HTN in liver transplant candidates.

Chronic hepatitis B virus infection is endemicin Asian communities in the United States. The purposeof the current study was to compare the antiviralefficacy of interferon-α2b in a groupof adult Asian patients chronically infected withhepatitis B with active replication compared to acontrol group of Caucasian patients treated with thesame regimen. Patients with entry aminotransferase (ALT)levels greater than three times the upper limit ofnormal received interferon-α2b, 5million units, subcutaneously daily for 16 weeks.Patients with pretreatment ALT levels 1.5-3 times theupper limit of normal received prednisone for a total of sixweeks prior to interferon starting at 60 mg daily withreduction in dosage by 20 mg every two weeks with atwo-week period between finishing prednisone and starting interferon-α2b. Eight(62%) of the 13 Asians and six (60%) of the 10Caucasians cleared HBeAg and HBV DNA from serum (NS). Bythe end of one year of follow-up after therapy, four(67%) of six Caucasian responders but none of the Asianresponders had cleared hepatitis B surface antigen fromserum (P < 0.05). Loss of serum markers of activereplication appeared less durable in the Asian responders compared to the Caucasians withreappearance of serum HBeAg in two (25%) of eight of theformer but only one (17%) of the latter group. Threeother Asian patients subsequently redeveloped HBeAg in serum. It is concluded that adultAsian-Americans have an identical initial response rateto antiviral therapy withinterferon-α2b; however, the responsemay be less durable and does not usually lead to loss of HBsAg.

A 58-year-old man underwent orthotopic liver transplantation for polycystic liver disease. Shortly after the procedure, it was discovered that the donor harbored a sarcoma of the aortic arch that had metastasized to the spleen, and bilateral renal cell carcinomas. The two sole organ recipients, our liver recipient and a lung recipient at another institution, were both listed for urgent retransplantation, which they received from the same second donor. The liver explant contained metastatic sarcoma. Twenty-four months survival following lung retransplantation has been previously reported. We report the 76-month disease-free survival in the liver recipient.

Interferon is currently the only approved medication in the United States for treatment of chronic hepatitis B and C infections. The mechanism of action of interferon and guidelines for its administration are reviewed. Important clinical studies involving its use in hepatitis B and C infections are discussed, and investigational therapies for chronic viral hepatitis are highlighted.

Primary biliary cirrhosis (PBC) has been considered to be a 'model auto-immune disease' for more than two decades. However, the underlying pathophysiology of PBC and the relationship with the associated serological abnormalities have been hitherto elusive. Beginning in 1987 with the cloning and subsequent identification of the mitochondrial autoantigens of PBC, progress has come rapidly and we can now sketch several potential pathogenic pathways through which disease occurs. More than 90% of patients with PBC produce autoantibodies to mitochondria, and the antoantigens involved have been identified as related components of the 2-oxo-acid dehydrogenase complexes (OADC), including the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2), the branched chain 2-oxo-acid dehdrogenase complex and 2-oxo-glutarate dehydrogenase complex, Protein X and E1 alpha. The cDNAs of each of the E2 subunits of OADC have been cloned and characterized. Moreover, the epitopes of the antimitochondrial antibodies (AMA) have been mapped at the highly conserved lipoyl domain E2 subunits. The use of recombinant peptides produced by these clones has greatly facilitated the detection of AMA. In addition, nucleotide sequence analysis of PDC-E2 specific human monoclonals and combinatorial Fabs strongly suggests that these autoantibodies are derived from clonal selection of a restricted set of somatically mutated immunoglobulin germline genes. Most interestingly, however, the use of monoclonal reagents to PDC-E2 has demonstrated that there is an increased expression of either PDC-E2, or a cross-reactive molecule, on the luminal surface of biliary epithelial cells in patients with PBC. These data provide a scenario to explain the tissue specific pathology associated with PBC and several interesting underlying pathophysiological mechanisms.

One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin ( or +2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trail was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated will ursodiol tended to develop a treatment failure less frequently that those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1.Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013.Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P.001). Decreases in SCr and survival were correlated (r(2) = .882; P.001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P.001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events.Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.

The clinicopathological features of 38 patients admitted consecutively for fulminant hepatic failure were studied. Histopathological material was reviewed in all patients. Both percutaneous and whole livers (either explanted or autopsy specimens) were available in 16 patients: whole livers only in 12 patients and biopsy specimens only in 10 patients. All patients were negative for antibodies to hepatitis C, whereas 24% had hepatitis B infection and 10% had adverse drug reactions. Livers from 75% of patients showed confluent hepatic necrosis. However, there was considerable variability in the extent of necrosis, and biopsy specimens from about 50% of the most severely affected livers showed only minimal bridging necrosis. In patients with massive hepatic necrosis, percutaneous liver biopsy specimens were frequently misleading because of regional inhomogeneities. Interestingly, five patients (13%) had established cirrhosis at the time of diagnosis. The best clinical predictors of survival were age and the maximal grade of encephalopathy. By contrast, neither the severity of confluent hepatic necrosis nor the etiology predicted the decision to transplant or the outcome. There were no differences in the histopathology corresponding to different etiologies. In summary, the approach to the patient with fulminant hepatic failure should be guided principally on clinical grounds, and further classification should be based on pathological and etiologic considerations. However, histological classification and prognosis based on percutaneous biopsy specimens alone may be misleading.

Objective. To describe a syndrome of severe progressive myopathy, cardiomyopathy, and gastrointestinal dysmotility in 2 patients with asymptomatic primary biliary cirrhosis (PBC) and circulating anti-mitochondrial autoantibodies, and to review pertinent literature concerning this syndrome. Methods. Clinical, electrophysiologic, serologic, and pathologic studies of the 2 affected patients were conducted. Results. Skeletal muscle involvement was manifested by progressive weakness of the proximal muscles, marked diaphragmatic dysfunction with consequent hypoventilation and respiratory failure, and moderately elevated levels of muscle-associated enzymes. Serum from both patients contained antimitochondrial antibodies that reacted with components of the mitochondrial keto acid dehydrogenase enzyme complex. Results of electromyography were consistent with a myopathic process. The microscopic and ultrastructural changes in the skeletal muscles were distinct from those of typical myositis, and were notable for striking subsarcolemmal aggregation of abnormal mitochondria in the absence of significant inflammation. Conclusion. Severe skeletal muscle, cardiac, and gastrointestinal pathology with abnormalities of the muscle mitochondria develops in a subset of patients with mild PBC and antimitochondrial antibodies. The pathogenesis of this syndrome is unclear, but may be related to the presence of the antimitochondrial autoantibodies.

The histologic diagnosis of extrahepatic biliary obstruction in the setting of orthotopic liver transplantation (OLT) may be complicated by nonobstructive factors, such as rejection, preservation injury, drug effects, and infection. Indeed, biopsy specimens from OLT patients frequently exhibit early posttransplant cholestasis, which is likely the result of several of these factors acting in concert. We reviewed the clinicopathologic features of 14 OLT patients whose biopsy specimens displayed prominent cholangitis with "obstructive"-type features. Cholangiograms, Doppler ultrasound examinations, and bacterial cultures were obtained in conjunction with all biopsy specimens. Despite histologic evidence of biliary obstruction, cholangiography revealed obstruction in only one case, leaks in four cases, and nine normal studies. Ten patients had severe systemic bacterial or cytomegalovirus infections. Biliary infection was documented in two cases. Hepatic artery occlusion was diagnosed in one case. The cholangitic pattern persisted in patients with unremitting infections, and two patients developed secondary biliary cirrhosis despite having consistently normal cholangiograms. Features of acute rejection or viral hepatitis were not observed on any biopsy specimen. The presence of this clinicopathologic spectrum was associated with a poor prognosis. Nine patients died and only four patients who responded to antibiotics survived. These findings demonstrate a striking cholangitic response to systemic infections in OLT grafts. The diagnosis of biliary obstruction in OLT liver biopsy specimens cannot be rendered without cholangiographic verification.

Orthotopic liver transplantation (OLT) has been used with increasing frequency as a definitive treatment for end-stage liver disease. Whereas the spectrum of pathology in the early posttransplant period is well documented, the clinicopathologic features of patients with late hepatic dysfunction are less clearly defined. In a series of 100 OLTs we identified 12 patients with progressive liver dysfunction 4 months after transplantation. Four patients succumbed rapidly to fulminant hepatitis 4 to 6 months following transplantation, three of whom had recurrent hepatitis B infection. One patient lost two successive grafts owing to hepatitis C. Liver biopsies were diagnostic for hepatitis in all cases. The outcome of the remaining eight patients with late hepatic dysfunction was grim. Their clinical courses were notable for intractable and progressive cholestasis. Five patients died and two others required retransplantation. Only one patient responded to increased immunosuppression with FK506. Ductopenia was a common feature of liver biopsies in these cases, but severe ductopenia (vanishing bile duct syndrome) was seen in the liver biopsies of only four patients. In contrast, occlusive arteriopathy and secondary ischemic changes were ubiquitous. In summary, the liver biopsy is a useful adjunct in the diagnosis of late OLT dysfunction, particularly in distinguishing recurrent viral hepatitis from chronic graft rejection. Centrilobular ischemic changes occur frequently in chronic rejection, whereas ductopenia may be difficult to document consistently.

Patients with primary biliary cirrhosis are well known for the presence of titer antibodies against dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex. We have taken advantage of a cDNA probe for dihydrolipoamide acetyltransferase to explore the possibility of polymorphism of the E2 subunit by probing genomic DNA from 38 patients with primary biliary cirrhosis and 26 healthy controls. To detect restriction fragment length polymorphism, DNA was digested with ten specific restriction enzymes that often detect polymorphism, including Bam HI, Bgl II, Eco RI, Hind III, Hinf I, Msp I, Pst I, Pvu II, Rsa I and Taq I. A Taq I polymorphism was found in 19 of 38 patients with PBC and 6 of 26 normal controls. In addition, using fluorescence in situ hybridization, the gene for dihydrolipoamide acetyltransferase was mapped on human chromosome 11 band q23.1. Interestingly, this region of the long arm of chromosome 11 is often associated with cytogenetic abnormalities, including translocations.

The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV-associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty-four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full-length genome sequences of the HAV from a cute liver failure sera were compared to those from self-limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non-liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were sub-genotype IB, acquired from the same study site over a 3.5-year period. Sub-genotype IB was found more frequently among acute liver failure cases compared to the non-liver failure cases (chi-square test, P

Before the identification of the major mitochondrial antigens of primary biliary cirrhosis as components of the 2-oxo-acid dehydrogenase enzyme family, mitochondrial autoantigens were believed to be extremely heterogeneous and were divided into nine subtypes termed M1 to M9. This classification was based on the data derived from the relatively nonspecific biochemical and immunological techniques that were available. After the cloning and definition of the major autoantigens, more than 95% of the sera of patients with primary biliary cirrhosis were found to react with components of the 2-oxo-dehydrogenase enzymes; these enzymes correspond to the old M2 classification. Two other “M” species, dubbed M4 and M9, have attracted significant attention because they have been postulated to be prognostic indicators and more recently have been tentatively identified respectively as sulfite oxidase (EC 1.8.3.1) and glycogen phosphorylase (EC 2.4.1.1). Indeed, patients with the “overlap syndrome” are reported to have antibodies to M4 and a poor prognosis, whereas patients with antibodies to M9 have a favorable prognosis. To address the significance and definition of M4 and M9, we performed in-depth studies of sera from 11 patients with the overlap syndrome, 75 patients with primary biliary cirrhosis, 19 chronic active hepatitis patients, 13 patients with primary sclerosing cholangitis, 10 patients with cholangiocarcinoma, 20 patients with systemic lupus erythematosus, 20 patients with alcoholic cirrhosis, 17 patients with scleroderma and 30 normal individuals, using techniques of ELISA, complement fixation, immunoblotting and enzyme inhibition. We report herein that we were unable to show any disease-specific reactivity toward the proposed M4 and M9 antigens. We offer potential explanations for false-positive readings and, most importantly, propose that the “M” nomenclature be discontinued and that autoantigens be designated by their proven and reproducible biochemical identity. (HEPATOLOGY 1992;16:1128–1136.)

objective: To review current concepts about the pathogenesis, clinical manifestations, and treatment of Wilson's disease, with an emphasis on recent developments. data identification: Published information was identified using MEDLINE and through extensive manual searching of bibliographies in identified sources. results: The basic biochemical alteration responsible for deranged hepatobiliary copper homeostasis in Wilson's disease has yet to be identified. The gene for Wilson's disease has been mapped to chromosome 13, but the function of its gene product has not yet been determined. The clinical manifestations of Wilson's disease are varied and often nonspecific and include a range of hepatic, neurologic, and psychiatric findings. Penicillamine remains the drug of choice for the treatment of Wilson's disease, but recent experience suggests that trientine and zinc may be safe, effective alternatives. All three drugs are probably safe for use in pregnant patients with Wilson's disease. Liver transplantation is the only effective treatment for Wilsonian fulminant hepatic failure and corrects the underlying metabolic defect. conclusions: Wilson's disease is a disorder of hepatobiliary copper excretion manifested predominantly by hepatic and neurologic copper toxicosis and inherited in an autosomal recessive pattern. Although the specific underlying biochemical defect remains to be defined, specific therapy is available and usually successful. Maintaining a high index of suspicion is critical in diagnosing this readily treatable inherited disease.

Primary biliary cirrhosis (PBC) has been described among various ethnic and racial populations in all parts of the world. However, the incidence and prevalence of PBC varies considerably in different geographic areas. It has the highest frequency in Northern Europe, is considerably lower in Japan and still lower in other parts of Asia. There has not hitherto been a detailed immunological profile of antimitochondrial antibodies according to geographic region. We have used recombinant or purified preparations from the 2-oxo-acid dehydrogenase enzyme complexes, the major mitochondrial autoantigens in PBC (PDC-E2, BCOADC-E2, OGDC, protein X and PDC-E1 alpha) to compare the reactivity of sera from either similarly staged sera from Japanese (n = 23) or American-Caucasian patients (n = 39) with PBC. In all cases, the first available sera following diagnosis was selected. Interestingly, only 65% of Japanese patients reacted by ELISA with PDC-E2 compared with more than 95% of the North American group. Moreover, the level of enzyme-inhibitory antibodies to PDC was lower in the Japanese. Our findings prompt the need for characterization of specific susceptibility genes and environmental factors in various parts of the world to clarify the etiology of PBC.

Adult respiratory distress syndrome (ARDS) complicating the course of fulminant hepatic failure is nearly always fatal without orthotopic liver transplantation. We report the case of a 50-year-old woman with fulminant hepatic failure and ARDS that resolved after her recovery from the acute liver failure without liver transplantation. The pathogenesis is discussed, particularly with regard to liver-lung interactions.

Hepatic encephalopathy (HE) is a syndrome of neuropsychiatric dysfunction caused by portosystemic venous shunting, with or without intrinsic liver disease. Patients with hepatic encephalopathy often present with the onset of mental status changes ranging from subtle psychologic abnormalities to profound coma. Several hypotheses have been proposed to explain the mental impairment associated with portosystemic shunting and liver disease. Clinicians diagnosing HE frequently have the opportunity to intervene and reverse severe HE, even hepatic coma. The recent advances in understanding and management of HE are the subject of this article.

The development of coagulopathy in acute liver failure (ALF) is universal. The severity of the coagulopathy is often assessed by determination of the prothrombin time and International Normalized Ratio (INR). In more than 1,000 ALF cases, the severity of the coagulopathy was moderate in 81% (INR 1.5–5.0), severe in 14% (INR 5.0–10.0), and very severe in 5% (INR > 10.0). Certain etiologies were associated with more severe coagulopathy, whereas ALF caused by fatty liver of pregnancy had the least severe coagulopathy. Management consisted of transfusions of FFP in 92%. Overall, FFP administered during the first week of admission amounted to 13.7 ± 15 units. Patients who received an ICP monitor had significantly more FFP transfused than those managed without ICP monitor (22.7 ± 2.4 vs. 12.3 ± 0.8 units FFP; P

BACKGROUND/AIMS: Soluble CD163 (sCD163) is a scavenger receptor shed in serum during inflammatory activation of macrophages. We investigated if sCD163 was increased and predicted outcome in acute liver failure (ALF). METHODS: Samples from 100 consecutive patients enrolled in the U.S. ALF Study Group for whom sera were available were collected on days 1 and 3, and clinical data were obtained prospectively. sCD163 levels were determined by ELISA. RESULTS: The median level of sCD163 was significantly increased in ALF (21.1mg/l (range 3.6-74.9)) as compared to healthy controls (2.3mg/l (0.65-5.6), p26mg/l) of sCD163 was significantly correlated with fatal outcome and might be used with other parameters to determine prognosis. Udgivelsesdato: 2007-Nov

Serum concentrations of alpha-fetoprotein (AFP), variably elevated during liver injury, have been suggested to be of prognostic importance in acute liver failure (ALF), higher values being associated with improved outcome. Using a nephelometric assay, we measured AFP in sera obtained on admission from 206 patients prospectively enrolled in the US ALF Study, and on day 3 in 162 of these patients. The AFP ratio was defined as the day 3 AFP concentration divided by that observed on day 1. Median (range) admission serum AFP in all patients was 8.1 (1-1,811) ng/mL and increased to 17.6 (1.1-1,162) ng/mL on day 3 (P0.001). Higher absolute levels were not associated with improved outcome. In fact, admission AFP levels were lower in survivors not receiving transplants than in those who died or were transplanted (P0.001), whereas there was no difference between the 2 groups on day 3 (P = 0.34). However, a rise in AFP values between day 1 and day 3 indicated a better prognosis: the AFP ratio was 2.2 (0.11-22.1) in spontaneous survivors and 0.87 (0.11-16.4) in nonsurvivors (P0.001). An increasing AFP level indicated by an AFP ratioor=1 was observed in 70 of 98 (71%) survivors, whereas a ratio1 was observed in 51 of 64 (80%) nonsurvivors. In conclusion, AFP values change dynamically during ALF. In this large prospective study, higher absolute values of AFP did not predict a favorable outcome, but a rising level of AFP over the first 3 hospital days frequently indicated survival.

Acute liver failure (ALF) due to hepatitis A virus (HAV) infection is an uncommon but potentially lethal illness. The aim of this study was to identify readily available laboratory and clinical features associated with a poor prognosis among ALF patients with HAV infection. The presenting features of 29 adults with anti-HAV IgM positive ALF enrolled in the ALFSG between 1998 and 2005 were reviewed. The HAV patients listed for transplantation by UNOS were also reviewed. Acute HAV accounted for 3.1% of patients enrolled in the ALFSG. At 3 weeks follow-up, 16 had spontaneously recovered (55%), 9 underwent transplantation (31%), and 4 had died (14%). A prognostic model incorporating 4 presenting features (serum ALT 2.0 mg/dL, intubation, pressors) had an AUROC for transplant/death of 0.899 which was significantly better than the King’s College criteria (0.623, P=.018) and MELD scores (0.707, P=.0503). Between 1988 and 2005, the frequency of patients requiring liver transplantation for HAV in the UNOS database significantly decreased from 0.7 % to 0.1% (P < .001). In addition, the proportion of HAV cases enrolled in the ALFSG significantly decreased from 5% to 0.8% (P = .007). In conclusion, the frequency of HAV patients enrolling in the ALFSG and being listed for liver transplantation in the United States has declined in parallel. A prognostic index consisting of 4 clinical and laboratory features predicted the likelihood of transplant/death significantly better than other published models suggesting that disease specific prognostic models may be of value in non-acetaminophen ALF.

Selection and timing of patient referral for liver transplant (LT) evaluation is important to optimize outcomes. The worse the decompensated liver disease, the higher the perioperative mortality. Thus, patients should ideally be referred for LT evaluation before they become debilitated and develop life-threatening complications. And, by implication, it is even more important to expeditiously refer for LT, even after the patient has decompensated, because significant improvements in mortality may still be possible.