Publications

BACKGROUND & AIMS

Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy.

METHODS

Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome.

RESULTS

Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]).

CONCLUSIONS

With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

UNLABELLED

The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by coadministration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by coadministering a dose of morphine low enough that it does not produce analgesia. After extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of 2 low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low-dose morphine may act as an anti-analgesia opioid receptor antagonist.

PERSPECTIVE

Previously, we reported that the nalbuphine produces both analgesic and anti-analgesic effects and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism.

OBJECTIVES

To determine whether inpatient palliative consultation services improve outcomes of care.

DESIGN

Retrospective telephone surveys conducted with family members of veterans who received inpatient or outpatient care from a Department of Veterans Affairs (VA) medical facility in the last month of life.

SETTING

Five VA Medical Centers or their affiliated nursing homes and outpatient clinics.

PARTICIPANTS

Veterans had received inpatient or outpatient care from a participating VA in the last month of life. One family member completed each survey.

MEASUREMENTS

The telephone survey assessed nine aspects of the care the patient received in his or her last month of life: the patient's well-being and dignity (4 items), adequacy of communication (5 items), respect for treatment preferences (2 items), emotional and spiritual support (3 items), management of symptoms (4 items), access to the inpatient facility of choice (1 item), care around the time of death (6 items), access to home care services (4 items), and access to benefits and services after the patient's death (3 items).

RESULTS

Interviews were completed with 524 respondents. In a multivariable linear regression model, after adjusting for the likelihood of receiving a palliative consultation (propensity score), palliative care patients had higher overall scores: 65 (95% confidence interval (CI)=62-66) versus 54 (95% CI=51-56; P<.001) and higher scores for almost all domains. Earlier consultations were independently associated with better overall scores (beta=0.003; P=.006), a difference that was attributable primarily to improvements in communication and emotional support.

CONCLUSION

Palliative consultations improve outcomes of care, and earlier consultations may confer additional benefit.