Time-dependent effects of chloroquine on pH of hepatocyte lysosomes

In vivo administration of chloroquine to rats caused an increase in the pH of hepatocyte lysosomes within 1 hr after administration with a return to baseline pH values by 3 hr; continued administration of chloroquine for up to 12 days was unaccompanied by any further changes in hepatocyte lysosomal pH. We interpret these data as evidence against a major role for an increase in the pH of hepatocyte lysosomes in CAC-induced phospholipidosis.     

Diagnosis and treatment of primary sclerosing cholangitis

PSC is a progressive chronic hepatobiliary disorder of unknown etiology for which no effective medical or surgical therapy now exists. This syndrome occurs most commonly in young men and is frequently associated with CUC. The diagnosis is best made utilizing endoscopic retrogradecopic retrograde cholangiography. Although liver histologic findings alone are infrequently diagnostic of PSC, it remains important to exclude other causes of chronic cholestasis. Although the etiology remains unknown, preliminary studies suggest that PSC is related to immunologic damage. Although viral infections can induce obliterative cholangitis in children, their role in the cause of PSC remains undefined. PSC progresses slowly from an asymptomatic stage to cirrhosis, portal hypertension, and premature death secondary to liver failure. Bile duct cancer appears to be a frequent complication of long-standing PSC. Since no therapy is of established efficacy, controlled clinical trials of both medical and surgical therapy should be encouraged. Fat-soluble vitamin deficiencies commonly occur in the advanced stages of PSC, and therefore serum levels of vitamins A, D, E, and prothrombin time should be monitored on a regular basis to prevent complications associated with these deficiencies. Liver transplantation is now a therapeutic option for the treatment of end-stage PSC. Palliative surgical biliary drainage procedures, proctocolectomy, and surgical decompressive shunts that increase the risk of liver transplants, therefore, should be avoided, if possible, in young PSC patients. If a total proctocolectomy is surgically indicated, we would strongly recommend performing a ileoanal pull-through procedure, thus, avoiding the formation of an abdominal ileostoma and the risk of developing bleeding peristomal varices.     

Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis

The effect of proctocolectomy on the primary sclerosing cholangitis that frequently is associated with chronic ulcerative colitis in patients with both conditions is unknown. We have studied prospectively the progression of clinical, biochemical, cholangiographic, and hepatic histologic features in 45 patients with both primary sclerosing cholangitis and chronic ulcerative colitis to compare these variables in the 20 patients who had undergone proctocolectomy with the 25 who had not. The two groups were similar initially with regard to clinical, biochemical, cholangiographic, and hepatic histologic findings. All patients were followed for a minimum of 1 yr and overall duration of follow-up was similar in both groups (4.1 vs. 3.9 yr). Clinically, new onset of hepatomegaly, splenomegaly, esophageal varices, and ascites did not differ in patients with and without proctocolectomy. Biochemically, the serial changes in bilirubin, alkaline phosphatase, aspartate aminotransferase, prothrombin time, and albumin were similar. Histologic progression on liver biopsy did not differ between groups, nor did changes on serial cholangiograms. Proctocolectomy also had no effect on survival. We conclude that proctocolectomy for chronic ulcerative colitis has no beneficial effect on the primary sclerosing cholangitis in patients with both diseases.     

Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

Hepatic artery and portal vein remodeling in rat liver: vascular response to selective cholangiocyte proliferation

Three-dimensional reconstruction of the biliary tree, hepatic artery, and portal vein in normal rats and rats fed alpha-naphthylisothiocyanate (ANIT), a compound that causes selective proliferation of epithelial cells (ie, cholangiocytes) that line the bile ducts, was performed. All hepatic structures in ANIT-fed rats branched 1.5 times more often than in normal rats, reflecting an increased number of segments, whereas the length of the biliary tree, hepatic artery, and portal vein remain unchanged. The length of the proximal vessel segments was uniform in both groups of rats whereas the length of distal segments decreased twofold in ANIT-fed rats, suggesting that small vessels preferentially undergo proliferation. In contrast, the length of all bile duct segments decreased twofold, suggesting that ANIT induced proliferation of all compartments of the biliary tree. The total volume of the biliary tree, hepatic artery, and portal vein was increased 18, 4, and 3 times, respectively, after ANIT feeding. The diameters of the bile ducts (range, 20 to 259 microm) and arterial (range, 21 to 276 microm) segments in ANIT-fed rats did not differ from normal rats (range, 21 to 245 microm and 20 to 265 microm, respectively). In contrast, the diameters of proximal venous segments in ANIT-fed rats were significantly less (316 +/- 68 micro m versus 488 +/- 89 micro m, P < 0.001). The data suggest that after experimentally induced cholangiocyte proliferation, the hepatic artery and portal vein also undergo marked proliferation, presumably to support the increased nutritional and functional demands of the proliferated bile ducts. The molecular mechanisms of these vascular changes remain to be determined.