Idiopathic adulthood ductopenia: case report and review of the literature.

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.

Clinical predictors of pulmonary hypertension in patients undergoing liver transplant evaluation.

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.

Jejunal telangiectasias as a cause of massive bleeding in a patient with scleroderma.

Telengiectasias (arteriovenous malformations) can be seen in scleroderma throughout the gastrointestinal tract, including the stomach, small bowel and colon. Massive gastrointestinal bleeding rarely results from these malformations in scleroderma. The case of a patient presenting with severe jejunal bleeding secondary to telangiectasias with special regard to the management is discussed. This case emphasizes the importance of endoscopic examination combined with mesenteric angiography in patients with scleroderma who present with a high index of suspicion of telangiectasias as a source of bleeding.

Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury.

In studies designed to simulate a clinical observation in which an individual became tolerant to normally lethal doses of acetaminophen (APAP), mice were pretreated with increasing doses of APAP for 8 days and challenged on day 9 with normally supralethal doses of APAP. These animals developed minimal hepatotoxicity after a challenge dose with a fourfold increase in LD50 to 1,350 mg/kg. The pretreatment regimen resulted in hepatic changes including: centrilobular localization of 3-(cysteine-S-yl)APAP protein adducts, selective down-regulation of cytochrome P4502E1 (CYP2E1) and CYP1A2 that produced the toxic metabolite, N-acetyl-p-benzoquinone imine, higher levels of reduced glutathione (GSH), centrilobular inflammation, and a fourfold increase in hepatocellular proliferation. The protection against the lethal APAP doses afforded by pretreatment is secondary to these changes and to the associated regional shift in the bioactivation of the APAP challenge dose from centrilobular to periportal regions where CYP2E1 is not found, protective GSH is more abundant, and where cell-proliferative responses are better able to sustain repair. This shift in APAP bioactivation results in less-intense covalent binding that is more diffuse and spread uniformly throughout the hepatic lobe, most likely contributing to protection by delaying the early onset of liver injury that has been generally associated with centrilobular localization of the adducts. Intervention of APAP pretreatment-induced cell division in mice with colchicine left them resistant to a 500-mg/kg (normally lethal) dose of APAP, but unable to survive a 1,000-mg/kg APAP challenge dose. The data demonstrate multiple mechanistic components to the protection afforded by APAP pretreatment. Whereas metabolic and physiological changes not dependent on cell proliferation are adequate to protect against 500 mg/kg APAP, these changes plus a potentiated cell-proliferative response are necessary for protection against the supralethal 1,000-mg/kg APAP dose. Furthermore, the data document an uncoupling of the traditional association between covalent binding and toxicity, and suggest that the assessment of toxicity following repeated or chronic APAP exposure must consider altered drug interactions and parameters besides those historically used to assess acute APAP overdose.