Biomedical subjects
Publications and source records attributed to C B Leevy.
In this work we will discuss three cutaneous markers of systemic disease. Acanthosis nigricans is the most widely known in this category. Cutaneous angiokeratomas are usually associated with enzyme defect disorders, such as Fabry's disease, and are linked in this work as a reactive pattern in hepatorenal failure. Mast cell disease may occur in a number of forms, often with systemic involvement.
OBJECTIVE: We wanted to know if alterations in plasma cobalamin (B12) concentration and B12 carriers, e.g., holotranscobalamins (holo TC), occur in blood and liver tissue from patients with severe alcoholic liver disease. Our purpose was to test the hypothesis that liver disease may disrupt B12 distribution. METHOD: Total B12, as well as B12 bound to transcobalamin I, II, III (holo TC), were measured to determine their concentration in plasma and in liver tissue; Poteriochromonas malhamensis--a protozoan reagent served to measure only metabolically active (true) B12. Total B12 as distributed in holo TC in plasma and liver tissue of healthy subjects (controls) were compared to patients with severe alcoholic liver disease. RESULTS: Severe liver disease initiates highly elevated B12 levels in plasma and a lowered liver tissue total B12 concentration. The percent of B12 distributed to holo TC II is significantly depleted during liver disease. In contrast, holo TC I and III are elevated in plasma during liver disease and contain more B12 than controls. Total B12 and B12 distributed to TC are lower in diseased liver tissue. CONCLUSION: Severe alcoholic liver disease involves leakage of total B12 from liver tissue into the plasma. Holo TC I and III concentration increases in plasma; this preserves the high plasma B12 from being excreted. However, plasma holo TC II B12 distribution is decreased, indicating that there is a depression of exogenous B12 entering the plasma and tissues. In severe liver disease, liver tissue B12 binding and storage by TC is disrupted and causes B12 to leak out of the liver into the circulation. Eventually liver disease could produce enough severe tissue B12 deficits to cause metabolic dysfunction despite elevated plasma total B12. Elevation of plasma B12, accompanied by a lowering of holo TC II distribution, seemed to be a useful index of liver disease severity suggesting preventive treatment.
Identification of a cDNA clone and the genome of hepatitis C virus in 1988-1989 allowed the development of clinical tests that are now used to detect and quantify hepatitis C virus. This has largely eliminated post-transfusion hepatitis C virus infection; however, the overall incidence of chronic hepatitis C and its complications has greatly increased because of its transmission by other means, lack of a protective vaccine, and inadequate virucidal therapy. Drug abuse is the most common cause of hepatitis C; an etiologic mechanism, however, remains unknown in one third of patients referred to the New Jersey Medical School Liver Center. Response to treatment depends on the viral subtype, immune reactivity of the host, and hepatic pathologic alterations. Many patients with hepatitis C improve or are cured by administering an interferon with or without ribavirin; patients refractory to these measures exhibit persistent elevation of serum cytokines and progressive liver disease. New measures, including protease inhibitors and adjunct immunotherapy, should increase effectiveness of therapy, diminishing hepatitis C virus-induced cirrhosis and hepatocellular cancer. Populations, including the underserved, who harbor and transmit hepatitis C virus require special assistance. This is best achieved by community support groups organized through medical schools, physician associations, and churches to help prevent, detect, and treat chronic hepatitis C.
Blood transfusions are common in patients with end-stage liver disease (ESLD), and their effects on sensitization, rejection, and liver graft survival are not well known. These effects were examined in 121 recipients of primary liver grafts, surviving > or = 30 days. Ninety-six (79%) patients received transfusions before transplantation. Transfusion recipients had significantly fewer severe or recurrent rejection episodes (18%), compared with patients who did not receive transfusions (42%, P=0.006), if the first transfusion was > or = 90 days before the transplant. Patients with alcoholic ESLD (n=49) had significantly fewer severe rejection episodes when compared with the nonalcoholic (n=72) patients (12% vs. 35%, P=0.004). The transfusion benefit was, however, more apparent and significant in the nonalcoholic (26% vs. 56% in nontransfused, P=0.02) than among the alcoholic recipients (6% vs. 25%, P=0.1). This finding is, most likely, due to a combination of a higher rate of severe rejection and the statistical power of the larger number of recipients in the nonalcoholic group. This finding is further corroborated by a multivariate analysis in which blood transfusions retained their benefit (P<0.05) independent of recipient's age and diagnosis. Graft and patient survival were not significantly different in the transfused versus nontransfused groups. Transfusion recipients had a higher panel antibody (11.4+/-23.4 vs. 2.7+/-8.1, P<0.02) but no increased risk of a positive crossmatch. In liver recipients, blood transfusions diminish the risk of rejection independent of recipient's age and the cause of ESLD.
Four Puerto Rican sisters had recurrent prolonged cholestasis of pregnancy without preexisting or intercurrent hepatic disorders. Available information was reviewed on the course, mechanism, and sequelae of prolonged recurrent cholestasis after 14 pregnancies in the 4 sisters. Etiologic, clinical, laboratory, radiological, and morphological studies of the liver and biliary tract were assessed. Each sister had contraceptive pill-induced pruritus. Prolonged recurrent cholestasis in the eldest sister was followed by cirrhosis and death. The second and third sisters had biopsy evidence of portal triaditis and fibrosis after five and three pregnancies, respectively. Intrahepatic cholestatic cirrhosis was present after three pregnancies in the youngest sister, necessitating an orthotopic liver transplantation; a posttransplantation pregnancy was also associated with prolonged cholestasis. Recurrent prolonged intrahepatic cholestasis of pregnancy was followed by periportal fibrosis or cirrhosis in 4 sisters. This finding suggests that patients with prolonged cholestasis after pregnancy should be followed up for evidence of ongoing liver disease, should be counseled on the potential of recurrence and disease progression in future pregnancies, and should alert family members at risk of possible occurrence of the syndrome.
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A number of genetic disorders have been described in limited form. We report a patient with precocious puberty, large irregularly shaped café-au-lait spots since birth and a diffuse scalp alopecia showing the cutaneous changes of fibrous dysplasia. Histologically, the hair follicles were replaced by convolutions of fibrous tissue. This is to our knowledge the first patient reported with an apparently localized cutaneous form of this syndrome, a pattern predicted by the recently described somatic mutation of the Gs alpha gene. This is the second patient reported to our knowledge with the cutaneous McCune-Albright syndrome and scalp alopecia, and the first with diffuse scalp alopecia, the latter being the presenting sign. We believe that the differential diagnosis of both localized and diffuse alopecia should include the McCune-Albright syndrome.
Chylous ascites occurs when lymphatics are disrupted due to primary lymphatic disease, infection, malignancy, or chronic liver disease. It may also occur following inadvertent interruption of abdominal lymphatics during surgery involving retroperitoneal dissection. It is suggested by some that during liver transplantation, severed hepatic lymphatics should be ligated or stented to avoid post-operative pleural and abdominal accumulation of chylous fluid. The occurrence of chylous ascites and the need to ligate lymphatics after orthotopic transplantation was assessed in 180 consecutive patients subjected to this procedure. Pre-operative chylous ascites present in one patient resolved following transplantation. Three patients who required retroperitoneal dissection to complete the biliary anastomosis via choledochojejunostomy or perform a hepatic artery graft developed post-operative chylous ascites which rapidly resolved without complications. These findings indicate special attention to transacted hepatic lymphatics is not required during orthotopic liver transplantation. Chylous ascites rarely occurs after liver transplantation and its transitory development is due to retroperitoneal dissection.
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Diagnostic criteria and prognosis have been revised for patients with liver and biliary tract diseases. This information provides an improved knowledge base for new preventive measures, therapeutic modalities, and outcome research at UMDNJ-New Jersey Medical School Liver Center.
Alcoholism alone, or in combination with other etiologic factors, is a common cause of liver failure because of hepatitis, cirrhosis, and/or hepatocellular cancer. Encountered morphologic and functional alterations are due to immunologic reactivity to cell injury evoked by acetaldehyde, other noxious factors, and nutrient deficits. Less than 20% of subjects who consume over 90 g/d of ethanol for years develop progressive liver damage and cirrhosis. Alcoholism should be interrupted in patients with subclinical hepatic abnormalities. Although early alcoholic hepatitis and cirrhosis respond to abstinence and symptomatic therapy, available measures have little influence on functional and morphologic abnormalities in end-stage alcoholic liver disease. Resection is desirable for localized hepatocellular cancer, and liver transplantation should be considered for cirrhosis. Transplantation is appropriate for patients with uncomplicated end-stage alcoholic cirrhosis in whom evidence of liver failure can be controlled during a 6-month period of rehabilitation. Continuous psychosocial support is required to prevent recividism in the posttransplant immunosuppressed alcoholic.
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Investigations were undertaken to determine the effect on lymphocyte reactivity of treatment of primary biliary cirrhosis with ursodeoxycholic acid (UDCA). Eight patients with stage 2 and 6 with stage 3 primary biliary cirrhosis were observed. Patients were treated with 300 mg of UDCA three times daily for 1 to 3 years. UDCA reduced jaundice, pruritus, and serum alkaline phosphatase levels. Repeat liver biopsy showed a decrease in inflammation in 3 patients. One patient with stage 3 primary biliary cirrhosis had disease progression despite UDCA treatment. Phytohemagglutinin (PHA) and concanavalin A (con A) were added to mixed lymphocytes from 9 patients receiving UDCA before and after 1 year of treatment. T-cell reactivity was determined by evaluating tritiated thymidine incorporation into DNA. Patients exhibiting an improvement in liver function tests had a significant reduction in lymphocyte reactivity to these mitogens (P < .01). When UDCA was stopped, the response to PHA and con A returned to pretreatment levels, reflecting continued presence of immunologic abnormalities characteristic of primary biliary cirrhosis. UDCA's effect on lymphocyte reactivity appears to be due to a reduction of hydrophobic bile acids, since it does not alter response to mitogens in patients with a normal liver.
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1. The effect of long-term (20 wk) treatment of cyclosporine A (CyA) was studied in urine, blood, liver, kidney and pancreatic concentrations of acid-soluble carnitine and free myo-inositol in streptozotocin diabetic rats. 2. Diabetic rats excreted significantly higher concentrations of carnitine and myo-inositol; CyA prevented the urinary loss of carnitine but not myo-inositol. 3. Blood carnitine levels were not different between normal and diabetic rats, however, CyA significantly decreased these levels. Conversely, blood myo-inositol concentrations were higher in diabetic than in normal rats; CyA prevented this increase. 4. Hepatic concentrations of both carnitine and myo-inositol were increased in diabetic rats; CyA treatment caused even further increase. 5. Pancreas from diabetic rats contained less carnitine and myo-inositol compared to normal pancreas. CyA treatment did not affect pancreatic carnitine, but it normalized myo-inositol in diabetic rats. 6. The kidney carnitine or myo-inositol levels were not influenced either by diabetes or by CyA treatment. 7. These results suggest that CyA treatment causes changes in carnitine and myo-inositol concentrations in biologic fluids and certain tissues.
Chronic vitamin A intoxication in a 56-year-old female is reported. Some abnormal blood chemistries included elevated transaminase and alkaline phosphatase, increased cerebrospinal fluid and portal pressure, and elevated vitamin A in blood and liver. A liver biopsy indicated histologic evidence of perisinusoidal collagen deposition and noncoalescent fat droplets in Ito cells. Caution against the misdiagnosis of alcoholic cirrhosis for vitamin A intoxication is recommended.
Concentrations of acid-soluble L-carnitine and inositol were determined in heart, kidney, muscle, pancreas, liver, brain and blood of genetically diabetic obese db/db and their nondiabetic control C57BL/6J (CBL) mice. Results were compared to a group of diabetic and CBL mice fed ethanol (ETOH) 4 g/kg daily for 58-64 days. In CBL and db/db mice, heart muscle was found to have the greatest and brain the least content of carnitine. Diabetes caused a significant decrease in hepatic concentration of carnitine but did not affect carnitine concentration of heart, kidney, skeletal muscle, brain and pancreas. ETOH intake had no effect on carnitine content of any of the tissues studied. Free inositol content was highest in brain and lowest in skeletal muscle of CBL and db/db mice; diabetes or ETOH intake did not affect tissue inositol content. Except for liver, neither diabetes nor ETOH intake affects tissue carnitine or inositol concentration.