Jonathan M. Schwartz

Screening for Wilson Disease in Acute Liver Failure: A Comparison of Currently Available Diagnostic Tests

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF‐WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 μg/dL in all ALF‐WD patients measured (13/16), but were also elevated in non‐WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF‐WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD. (HEPATOLOGY 2008.)

Prevalence and Natural History of Alcoholic Liver Disease

Alcoholic liver disease is a major cause of morbidity and mortality among people who drink excessive amounts of alcohol. There is a spectrum of liver injury that ranges from steatosis to varying stages of hepatic fibrosis and cirrhosis, with subsequent risk for hepatocellular carcinoma. Steatohepatitis can occur at any stage of disease.

Elevated troponin I levels in acute liver failure: Is myocardial injury an integral part of acute liver failure?

Although rare instances of cardiac injury or arrhythmias have been reported in acute liver failure (ALF), overall, the heart is considered to be spared in this condition. Troponin I, a sensitive and specific marker of myocardial injury, may be elevated in patients with sepsis and acute stroke without underlying acute coronary syndrome, indicating unrecognized cardiac injury in these settings. We sought to determine whether subclinical cardiac injury might also occur in acute liver failure. Serum troponin I levels were measured in 187 patients enrolled in the US Acute Liver Failure Study Group registry, and correlated with clinical variables and outcomes. Diagnoses were representative of the larger group of >1000 patients thus far enrolled and included 80 with acetaminophen‐related injury, 26 with viral hepatitis, 19 with ischemic injury, and 62 others. Overall, 74% of patients had elevated troponin I levels (>0.1 ng/ml). Patients with elevated troponin I levels were more likely to have advanced hepatic coma (grades III or IV) or to die (for troponin I levels >0.1 ng/ml, odds ratio 3.88 and 4.69 for advanced coma or death, respectively). Conclusion: In acute liver failure, subclinical myocardial injury appears to occur more commonly than has been recognized, and its pathogenesis in the context of acute liver failure is unclear. Elevated troponin levels are associated with a significant increase in morbidity and mortality. Measurement of troponin I levels may be helpful in patients with acute liver failure, to detect unrecognized myocardial damage and as a marker of unfavorable outcome. (HEPATOLOGY 2007;45:1489–1495.)

Predictive value of actin‐free Gc‐globulin in acute liver failure

Serum concentrations of the actin scavenger Gc‐globulin may provide prognostic information in acute liver failure (ALF). The fraction of Gc‐globulin not bound to actin is postulated to represent a better marker than total Gc‐globulin but has been difficult to measure. We tested a new rapid assay for actin‐free Gc‐globulin to determine its prognostic value when compared with the Kings College Hospital (KCH) criteria in a large number of patients with ALF. A total of 252 patients with varying etiologies from the U.S. ALF Study Group registry were included; the first 178 patients constituted the learning set, and the last 74 patients served as the validation set. Actin‐free Gc‐globulin was determined with a commercial enzyme‐linked immunosorbent assay kit. The median (range) actin‐free Gc‐globulin level at admission for the learning set was significantly reduced compared with controls (47 [0‐183] mg/L vs. 204 [101‐365] mg/L, respectively, P < 0.001). Gc‐globulin levels were significantly higher in spontaneous survivors than in patients who died or were transplanted (53 [0‐129] mg/L vs. 37 [0‐183] mg/L, P = 0.002). A receiver operating characteristic curve analysis showed that a 40 mg/L cutoff level carried the best prognostic information, yielding positive and negative predictive values of 68% and 67%, respectively, in the validation set. The corresponding figures for the KCH criteria were 72% and 64%. A new enzyme‐linked immunosorbent assay for actin‐free Gc‐globulin provides the same (but not optimal) prognostic information as KCH criteria in a single measurement at admission. Liver Transpl 13:1324–1329, 2007.

Model for End-stage Liver Disease score fails to predict perioperative outcome after hepatic resection for hepatocellular carcinoma in patients without cirrhosis

BACKGROUND The Model for End-stage Liver Disease (MELD) score was developed to reflect the hepatocellular reserve in patients with cirrhosis. We hypothesized that the MELD score would not be predictive of perioperative outcome after hepatic resection in patients without cirrhosis. METHODS We performed a case-control study of all consecutive patients from 1995 through 2005 undergoing hepatic resection for HCC. RESULTS Group A (21 patients without cirrhosis) had a mean age of 57 years, which was similar to control group B (25 patients with cirrhosis), with a mean age of 60 years. The mean tumor size in group A was 9.8 cm compared with that of group B, which was 4.8 cm (P = .03). The American Joint Committee on Cancer stage in group A was I in 14%, II in 5%, and III in 81% versus I in 48%, II in 16%, and 111 in 36% in group B (P = .002). Eighty-six percent of group A patients had a major hepatic resection (>2 segments) compared with 40% in group B (P = .001). The perioperative morbidity and mortality were 24% and 4.8%, respectively, in group A compared with 64% (P = .006) and 20% (P = .12) in group B. The mean preoperative, postoperative, and delta MELD scores were 7.0, 13.0, and 5.0, respectively, in group A compared with 9.6, 16.8, and 7.2 in group B (P = NS). In group A, none of the MELD score parameters accurately predicted perioperative outcomes despite a higher number of patients who had major hepatic resection. In group B, a preoperative MELD score of 9 or greater was associated with a higher overall perioperative morbidity (84% vs 41%, P = .03). Perioperative mortality (n = 6; 13%) was significantly higher in patients with a postoperative MELD score of 15 or higher (P = .02) and a delta MELD score of 10 or higher (P = .03). CONCLUSIONS Perioperative MELD score fails to predict perioperative outcomes after hepatic resection for hepatocellular carcinoma in patients without cirrhosis. Other predictive parameters need to be developed for this group of patients.

Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: incidence, causes, and outcome.

Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987–1997: incidence, causes, and outcome

Cardiopulmonary consequences of transjugular intrahepatic portosystemic shunts: Role of increased pulmonary artery pressure

Goals: To determine whether increased pulmonary artery pressure (PAP) following transjugular intrahepatic portosystemic shunting (TIPSS) results in short-term mortality or cardiorespiratory complications. Background: TIPSS is frequently performed for complications of cirrhosis. PAP increases following TIPSS; however consequences of this phenomenon are unknown. Study: Demographics, disease severity and etiology were recorded among patients undergoing TIPSS. PAP before and following TIPSS were measured and the relationship between PAP before and after TIPSS, and subsequent cardiorespiratory complications and mortality was examined. Results: Thirty-one patients were enrolled (mean age 53 years, 74% men, 55% Child-Pugh class C cirrhosis). TIPSS was performed for variceal bleeding in 84% of cases. Ten patients (32%) died 5–20 days following TIPSS. PAP increased significantly following TIPSS (mean 20.8 mm Hg pre-TIPSS (95% CI 18.2–23.4) to 26.9 mm Hg post-TIPSS (95% CI 24.2–29.6, P = 0.0016). Congestive heart failure developed in 4 patients (13%), sepsis in 4 (13%), and ARDS in 8 (26%). Increased PAP following TIPSS was not associated with early mortality (P = 0.13), CHF (P = 0.31), or ARDS (P = 0.43). ARDS was the only significant predictor of short-term mortality following TIPSS (OR 18.7, P = 0.02 (95% CI: 1.5–232). Conclusion: PAP increases after TIPSS and cardiorespiratory complications are common, yet unrelated to increased PAP. ARDS is independently associated with increased risk of mortality after TIPSS.

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

Data about adverse events are needed to optimise telaprevir‐based therapy in a broad spectrum of patients.

Impact of locoregional therapy and alpha‐fetoprotein on outcomes in transplantation for liver cancer: a UNOS Region 6 pooled analysis

Liver transplantation (LT) provides optimal long‐term disease‐free survival for hepatocellular carcinoma (HCC). High pre‐LT alpha‐fetoprotein (AFP) has been associated with HCC recurrence, but it is unclear whether a drop in AFP or locoregional therapy impacts survival/recurrence after LT. LT‐recipients transplanted for HCC in three centers (UNOS Region 6) were reviewed (2006–2009) for demographics, tumor characteristics, locoregional therapy, AFP, recurrence, and survival. Among 211 LT recipients (mean age 56.4 yr, 83% male, mean MELD 12.2), 94% met Milan criteria and 61% received locoregional therapy. Mean disease‐free survival (DFS) was 1549.7 d, and 84% are currently alive. Factors affecting DFS included recurrence (RR, 0.074; 95% CI, 0.038–0.14), normal peak AFP (29.6, 95% CI, 2.96–296.3), peak AFP >400 (RR, 0.15; 95% CI, 0.03–0.73) and AFP at LT >400 (RR, 15.5; 95% CI, 2.4–100.5). Twenty‐one patients had recurrence and were more likely beyond Milan criteria (5/23(21%) vs. 8/220 (4%), p = 0.0038), with peak AFP >400 and AFP at LT >400 (p = 0.001). Locoregional therapy did not affect mean DFS (1458.0 vs. 1603.8 d, p = 0.05) or recurrence (12.5% vs. 6%). Predictors of recurrence were similar to previous studies, including high AFP and tumor outside Milan criteria. While locoregional therapy itself did not affect DFS/recurrence, a decrease in AFP pre‐transplant appears to positively influence outcomes in those who received locoregional therapy.

Wound healing in normal and analbuminemic (NAR) rats

It has been suggested by several investigators that hypoalbuminemia results in impaired wound healing. In most studies, however, hypoalbuminemia is a manifestation of malnutrition or underlying liver disease. In this study, we examined the effect of isolated hypoalbuminemia on wound healing. Analbuminemic (NAR) rats which are Sprague-Dawley mutants with trace levels of plasma albumin due to a defect in albumin synthesis were studied. Adult NAR and Sprague-Dawley rats (n = 10 each) underwent a 7 cm dorsal skin incision and implantation of a polyvinyl alcohol sponge subcutaneously under pentobarbital anesthesia. Seven days postoperatively all rats were killed with ether, the wounds were excised, and breaking strength was measured. Sponge hydroxyproline content was determined colorimetrically. There were no significant differences in wound breaking strength (fresh or formalin fixed) or sponge collagen content between the Sprague-Dawley and analbuminemic rats. We conclude that isolated hypoalbuminemia has no detrimental effect on would healing in rats.