Biomedical subjects
Publications and source records attributed to H L Sharp.
Women with severe liver disease often have amenorrhea that resolves as liver disease abates. We describe three patients with mild to moderate chronic liver disease and amenorrhea. In each case amenorrhea resolved when spironolactone therapy was discontinued. We suggest that spironolactone, an androgen inhibitor, may also cause reversible amenorrhea.
Liver transplantation is now accepted as the treatment of choice for tyrosinemia type I (hereditary tyrosinemia). In an effort to determine whether any factors in these patients would aid in predicting optimal timing of the transplant procedure, we evaluated several clinical, biochemical, and radiographic parameters in five successive patients undergoing liver transplant for tyrosinemia type I at the University of Minnesota. All five patients evidenced prolonged periods of clinical and metabolic stability with dietary therapy and four of five remained stable at the time of evaluation for transplantation. Nevertheless, all five suffered significant and unexpected complications of tyrosinemia prior to the time of liver transplant. Four developed renal stones, two were in liver failure, and one developed a neurologic crisis that left him completely paralyzed. Hepatocellular carcinoma was found in one of the five at transplant. We could identify no clinical, biochemical, or radiographic study that was predictive of the likelihood of significant complications of the disorder. Survival from the transplant procedure itself was 100%. The inability to predict or prevent significant complications of tyrosinemia and the favorable outcome from transplantation lead us to recommend liver transplant for all patients with tyrosinemia type I by 12 months of age.
In an effort to better understand chronic liver transplant rejection, we studied 110 children and adults who survived for at least 2 mo after the transplant procedure. Chronic rejection was defined using a combination of clinical and histopathological criteria and was diagnosed in 10 of the 110 patients for an incidence of 9.1%. All 10 patients were children with the mean age 3.4 yr vs. 21.7 yr for patients without chronic rejection (p less than .001). Males and females were equally represented, and nine received a liver from a gender-matched donor. Four patients were non-Caucasian, resulting in an incidence of 21.7% in non-Caucasian recipients vs. 6.6% in Caucasian recipients (p less than .05). All chronic rejection patients received a liver from an ABO-compatible donor. T-cell crossmatch was negative in all patients in whom it was assessed, and no significant disparity in either the class I or class II human leukocyte antigen loci was noted. Patients who had chronic rejection experienced acute rejection earlier, 11 days vs. 16 days (p less than .05), than patients who did not. In 8 of 10 patients, chronic rejection appeared to evolve directly from early episodes of acute rejection that were unresponsive to immunosuppressive therapy. Two distinct histological presentations were noted. One was progressive loss of bile ducts without hepatocellular injury (four patients), and the other was characterized by worsening ischemic hepatocellular damage and fibrosis (six patients) in addition to severe ductular injury. The first was associated with a more benign clinical course, the second with rapidly deteriorating hepatic function. Three patients recovered spontaneously 9 to 14 mo after transplant, one died awaiting a donor for retransplant, and five had retransplants. We conclude that chronic rejection after the operation is a relatively uncommon complication of liver transplantation with a variable clinical course and unpredictable outcome.
We reviewed the clinical presentation, subsequent course, and outcome of 98 patients with alpha 1-antitrypsin deficiency seen at our institution during the past 20 years to obtain answers to the following questions: (1) What prognostic factors aid in determining the course of liver disease in affected patients? (2) When is the appropriate time for referral to a liver transplant center? (3) Does breast-feeding prevent chronic liver disease? (4) What is the incidence of severe liver disease in family members? Our analysis revealed that the initial values of alanine aminotransferase, prothrombin time, and trypsin inhibitory capacity may have prognostic value. During clinical follow-up the recurrence or persistence of hyperbilirubinemia along with deteriorating results of coagulation studies indicated the need for liver transplantation because of imminent poor outcome. Girls had a worse prognosis than boys. Initial breast-feeding versus feeding of commercial formulas did not influence overall overcome. The incidence of significant liver disease among "at risk" siblings was 21% (3/14); if one assumes mendelian inheritance from heterozygous parents, the overall risk for siblings in our families was 5%.
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The source of population renewal for Kupffer cells (KC), the major antigen-presenting cells of the liver, remains controversial. Using a well-described murine bone marrow transplantation (BMT) model in which the donor and recipient are disparate at the major histocompatibility complex (MHC), we have studied (a) the source of KC renewal by genotypic analysis, cell surface (class II or Ia) antigens, and immune function assays; (b) the level of KC Ia expression post-BMT in transplant recipients; and (c) the capacity of newly repopulating KC to present antigen to an Ia-restricted T cell clone of donor Ia type. Kupffer cell engraftment, as assessed by each of these three methods, was noted to be predominantly of donor marrow origin by day 21 post-BMT. Cell surface Ia expression was comparable to that of nontransplanted controls of the same strain as donor mice. Within 7 days post-BMT, KC were mature antigen-presenting cells. We conclude that KC rapidly repopulate the liver from donor bone marrow post-BMT, and these macrophages are able to interact with T lymphocytes in an immunocompetent manner.
Hereditary tyrosinemia type I presents with either acute hepatic failure in the neonatal period or later in infancy with progressive liver dysfunction secondary to cirrhosis. The inevitably fatal outcome in those children with the chronic form has been transformed with the advent of liver transplantation. Native livers from five children who received allografts were studied pathologically and compared with earlier hepatic biopsies in two of these patients that had been performed several years before transplantation. Our findings support the conclusion that a sequence of morphologic changes from the initial micronodular cirrhosis through an intermediate mixed cirrhotic pattern to macronodular cirrhosis occurs. The micronodular phase is transitory, over a period of only a few months, since mixed micronodular macronodular cirrhosis was already present in the livers of children who received transplants by 11 months of age. Focal hepatocellular dysplasia was present in one of the livers with mixed cirrhosis but was not identified in the other two cases. Macronodular cirrhosis accompanied two cases of hepatocellular carcinoma in this study. In order to preclude the latter complication, liver replacement is necessary before the age of 2 years.
In most institutions, a percutaneous kidney biopsy is considered a safe procedure. However, multiple complications involving other organ systems have been reported. We present two cases in which complications following renal biopsy involved the gastrointestinal tract. The first case was manifested by pancreatitis and the formation of a pancreatic pseudocyst. The second case involved perforation of the small bowel. Neither patient required surgical intervention; both were managed conservatively and the outcome was excellent.
The genes encoding three distinct serine protease inhibitors (Spi) have been cloned from rat liver. These inhibitors are highly homologous with each other and are similar to alpha 1-antitrypsin at the nucleic and amino acid sequence level. Although previous investigators have examined the regulation of the Spi 2 locus by inflammation, the use of various techniques and the complexity of this genetic locus have led to incomplete and somewhat confusing results. Oligonucleotide probes specific for Spi 2.1, Spi 2.2, Spi 2.3, and a 3' mouse cDNA probe for alpha 1-antitrypsin mRNA were used to measure these mRNA after induction of inflammation with subcutaneous turpentine in Fischer rats. alpha 1-Antitrypsin mRNA increased 1.8-fold, and Spi 2.2 increased 7-fold. In contrast, Spi 2.1 and 2.3 mRNA sequences decreased fourfold. The maximal changes occurred between 24 and 48 h after inflammation, with a gradual return toward normal over the next 4 days. Since Spi 2.1, Spi 2.3, and alpha 1-antitrypsin mRNA sequences are responsive to growth hormone, two other growth hormone-responsive mRNA sequences, alpha 2u-globulin and insulin-like growth factor I, were measured, and they also decreased after induction of inflammation. The results of this study show that, despite a marked similarity of nucleotide sequence, Spi 2.1 and 2.3 genes respond very differently from Spi 2.2 and alpha 1-antitrypsin to both growth hormone and inflammation. We speculate that the functions of Spi 2.1 and 2.3 products are different from those of Spi 2.2 and alpha 1-antitrypsin and may involve the regulation of growth.
Growth hormone regulates the hepatic mRNA levels of alpha 1-antitrypsin and two contrapsin-like mRNAs in the rat. To determine whether growth hormone regulates similar serine protease inhibitors in humans, we measured serum alpha 1-antitrypsin, alpha 1-antichymotrypsin, and antithrombin III by radioimmunodiffusion in 16 growth hormone deficient children before and after growth therapy. Of the 19 determinations made, 17/19 showed an increase in alpha 1-antitrypsin after administration of growth hormone, 198.6 +/- 39.1 mg/dl before growth hormone and 239.4 +/- 44 mg/dl after growth hormone (p = 0.005). Specificity of the response for alpha 1-antitrypsin was indicated by the fact that neither alpha 1-antichymotrypsin or antithrombin III values changed after growth hormone (p = 0.6 and 0.5, respectively). These data are compatible with the hypothesis that growth hormone regulates serine protease inhibitors in humans and suggests that investigation of other members of the serpin gene family might prove fruitful in defining additional growth hormone target genes.
Low IGF-I levels are found in patients with chronic liver disease, but it is not known whether these reductions in IGF-I are secondary to hepatic dysfunction or to malnutrition. To determine whether malnutrition associated with hepatic dysfunction causes the decrease in these levels, serum and liver IGF-I concentrations and liver IGF-I mRNA content were compared in three groups of Sprague-Dawley rats: 15 rats underwent bile duct obstruction; 10 rats were sham-operated and pair-fed with operated rats to control for nutritional status; and 12 rats were sham-operated controls fed ad libitum. In addition, IGF-I peptide and mRNA were compared with food intake, crude nitrogen balance, total wt gain, tail length increase and leg muscle wt. All the parameters were lower in cholestatic and nutritionally deprived animals than in control animals (p less than 0.001). There was no difference in serum and hepatic IGF-I and liver IGF-I mRNA values between the 10 cholestatic and pair-fed animals, despite lower crude nitrogen balance, tail length gains, and leg muscle wt in the bile duct-obstructed animals. These studies suggest that in chronic bile duct obstruction, the low serum and hepatic IGF-I levels are primarily due to decreased food intake and appear unrelated to cholestatic liver disease itself. However, factors in addition to suboptimal nutrition and decreased IGF-I levels must also contribute to cholestasis-induced growth failure.
The epithelium of the biliary tree is involved in the response to numerous liver disease processes including immunologic destruction during liver transplant rejection and liver graft-versus-host disease after bone marrow transplantation. Furthermore, very little is known concerning the function of this previously inaccessible epithelium, because attempts to isolate and culture biliary cells have been unsuccessful until recently. We present a method for the isolation and culture of bile ductular cells from mice with external bile duct obstruction. Over 85% of the isolated cells stain positive for cytokeratin 19, which is characteristic of murine biliary epithelium. Incubation with recombinant murine gamma-interferon resulted in increased class II antigen expression on the isolated cell surface. When these cells were placed, on a basement membrane matrix, they formed duct-like structures composed of cells that had the morphologic characteristics of bile ductular epithelium when examined by transmission electron microscopy. The ability to isolate murine biliary epithelium that forms duct-like structures will be useful for the in vitro study of biliary epithelial characteristics and injury.
A gastric bezoar complicated the postoperative course of three children following successful hepatic transplantation. Two patients had evidence of extremely erratic absorption of the cyclosporine (CSA) used for immunosuppression. Gastric bezoars usually occur in patients with gastric dysmotility and/or patients ingesting poorly digestible material. Although several factors may contribute to bezoar formation after hepatic transplantation, a major predisposing factor may be the administration of the large quantities of olive oil required for solubilization of CSA.
Liver transplantation has revolutionized the field of pediatric hepatology. The present status of this therapy is reviewed in this article from a nonsurgical perspective.
A 3-month-old infant presented with ascites, anemia, minimal rectal bleeding, and thrombocytopenia. He was found to have several hundred small cavernous hemangiomas of the colon and peritoneal surfaces. Treatment consisted of laser surgery, subtotal colectomy, and steroids. A brief review of the literature on intestinal hemangiomatosis is included as well as the complications of the disease and current therapy.
We evaluated the effects of pituitary dependent hormones on alpha 1-antitrypsin in male rats. Hepatic alpha 1-antitrypsin mRNA was measured by in vitro translation and by specific hybridization with a mouse cDNA alpha 1-antitrypsin probe. Hypophysectomy caused a 50-75% decrease in serum elastase inhibitory capacity (measuring functional alpha 1-antitrypsin) and hepatic alpha 1-antitrypsin mRNA content. In hypophysectomized animals, no increase in elastase inhibitory capacity or alpha 1-antitrypsin mRNA levels by translation was found when met-human growth hormone alone or corticosterone, dihydrotestosterone and thyroxine were given together. Growth hormone increased alpha 1-antitrypsin mRNA by hybridization to a small extent. Addition of growth hormone to the combination of corticosterone, dihydrotestosterone, and thyroxine increased serum elastase inhibitory capacity and alpha 1-antitrypsin mRNA. We conclude that growth hormone acts synergistically with the other pituitary dependent hormones to regulate serum and hepatic mRNA levels of alpha 1-antitrypsin.
A 53-yr-old man with a rare form of partial alpha 1-antitrypsin deficiency, PiM1/PiMduarte, died of endstage cirrhosis. Typical cytoplasmic alpha 1-antitrypsin globules were present in the hepatocyte cytoplasm. Initial protease inhibitor phenotyping on the patient was reported as normal PiM1 in more than one laboratory. This case emphasizes the diagnostic importance of alpha 1-antitrypsin and illustrates the point that protease inhibitor phenotyping without family genotyping may be misleading in heterozygous patients with liver disease.
Three patients with hereditary tyrosinemia type I were examined before and after liver transplantation to assess the role of extrahepatic tissues in the biochemical disorders of this disease. Before transplantation the three patients excreted excessive amounts of succinylacetoacetate (SAA), succinylacetone (SA), tyrosyl acidic compounds, and 5-aminolevulinate (ALA). The activity of 5-aminolevulinate dehydratase (ALA-D) in red blood cells was markedly inhibited (1% to 5% of control) in the three patients. Successful liver transplantation resulted in decreased excretion of urinary SAA plus SA, tyrosyl acidic compounds, and ALA. Two of the patients continued to excrete significant amounts of SAA plus SA, whereas those compounds were undetectable in the urine of the third patient. Tyrosine loading resulted in increased excretion of SAA plus SA in two patients, but those compounds remained undetectable in the third. All three patients continued to excrete higher than normal amounts of ALA, but the activity of ALA-D in red blood cells returned to normal after transplantation, indicating marked clearance of SA from the blood. Liver transplantation may not totally correct the biochemical abnormalities of hereditary tyrosinemia. It is likely that the kidney is the source of persistent biochemical aberrations in the urine without significant effects on the blood. Our results suggest the existence of heterogeneity for renal involvement in hereditary tyrosinemia.