Jeffrey M. Rank

Isolation of replication-competent molecular clones of visna virus

Visna virus is the prototypic member of a subfamily of retroviruses responsible for slow infections of animals and humans. As a part of our investigation of the functions of viral gene products in virus replication, we have isolated three infectious molecular clones and determined the complete nucleotide sequences of two of the clones. We have also characterized the progeny of the biologically cloned viral stocks and of the infectious clones and document considerable heterogeneity in plaque size and antigenic phenotype of the former that is reduced to near homogeneity in the progeny of the infectious clones. It thus should now be possible to trace the emergence of antigenic variants of visna virus as well as ascribe defined functions to structural and regulatory genes of the virus in determining neurovirulence and the slow tempo of infection.

Early liver transplantation is indicated for tyrosinemia type I

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.

Hematin therapy in late onset congenital erythropoietic porphyria

Hematin therapy is established in the treatment of the hepatic porphyrias, repressing 5-aminolaevulinic acid (ALA) synthase, and thereby decreasing porphyrin production (Pierach, 19 82). One previous study reported hematin-mediated reduction in porphyrin excretion in a patient with congenital erythropoietic porphyria (CEP) first manifested at birth (Watson et al, 1974). We therefore attempted hematin therapy in an adult onset CEP patient. This is the sixth report of adult onset of this disorder (Deybach et al, 1981). The patient was a 5 1-year-old male of Eastern European descent with no family history of porphyria. He presented with a complaint of fatigue and blistering of sun-exposed skin. Laboratory evaluation revealed normal serum aspartate aminotransferase (GOT), alanine aminotransferase (GPT) alkaline phosphatase (AP), decreased haemoglobin (10.6 g/ dl) and elevated urinary coproporphyrin (COP) (3.46 mg/24

Hematin therapy in children with protoporphyric liver disease

Protoporphyria is a genetic disorder of porphyrin metabolism in which a deficiency of ferrochelatase activity causes excessive accumulation and excretion of protoporphyrin (1,2). Protoporphyrin is excreted in bile, and its deposition in the liver impairs hepatic structure and function (3,4). As a co

Endoscopic variceal ligation in pediatric patients with portal hypertension secondary to liver cirrhosis

BACKGROUND Endoscopic variceal ligation is the initial treatment of choice in the management of esophageal varices. Few reports include its use in the pediatric population. We review our experience with this therapeutic modality in pediatric patients with end stage liver disease and esophageal varices. METHODS We reviewed the medical records of pediatric patients with end stage liver disease who underwent endoscopic variceal ligation from January 1994 until December 1996. RESULTS Thirty-two endoscopic variceal ligation procedures were performed in six pediatric patients during the period of study. In all patients, the esophageal varices classification was improved at the end of treatment. Only one patient had an episode of bleeding from esophageal varices during the period of study; only one patients had a complication associated with endoscopic variceal ligation. CONCLUSIONS Endoscopic variceal ligation is feasible, safe, and effective for the management of esophageal varices in pediatric patients with end stage liver disease.

Hematin therapy for the neurologic crisis of tyrosinemia

Hereditary tyrosinemia (tyrosinemia type I) is an autosomal recessive disorder caused by a defect of the final enzyme in tyrosine metabolism. The disease is associated with renal tubular defects, acute and chronic liver failure, and hepatocellular carcinoma. An elevation in serum 6-aminolevulinic acid concentration is common and is due to competitive inhibition of ALA dehydrase by succinylacetone, a metabolite of tyrosine degradation. 1 A syndrome of acute neurologic crises, which has striking similarity to the acute porphyrias, is seen in as many as 40% of the children with this disorder. 2 As in the acute porphyrias, the episodes of acute neuropathy associated with tyrosinemia are best correlated with ALA excretion. 2 Hematin suppresses ALA synthase, the first committed step in heme synthesis. 3 Clinical studies in patients with porphyria have established the efficacy of hematin in decreasing ALA excretion and the improvement of clinical symptoms after intravenous administration. 4 The drug has few side effects and has been used without major complications in the treatment of numerous patients with acute porphyria. 4 We describe a case of severe neurologic crises associated with extremely high serum ALA levels in a child with tyrosinemia I. We elected to treat this patient with hematin, followed by liver transplantation. We believe this to be a rational course given the marked similarities of this disorder to the acute porphyrias.

Liver in disorders of porphyrin metabolism.

The liver has two important roles in porphyrin metabolism. It is a major site of synthesis of porphyrins because these compounds are precursors of haem, which is the prosthetic group for the mitochondrial cytochromes and cytochrome P450. It also excretes porphyrins into bile. The partitioning of a porphyrin between urine and bile correlates with the number of carboxylate groups in the compound, hence with its water solubility. Uroporphyrin, which has eight carboxylate groups and is the most water soluble, is excreted predominantly in the urine. Coproporphyrin has four carboxylate groups and is found in both urine and bile. Protoporphyrin, which is poorly water soluble because it has only two carboxylate groups, is excreted only in bile. The porphyrias are metabolic disorders in which inborn errors of haem biosynthesis cause excessive accumulation and excretion of porphyrins and porphyrin precursors. In five of the porphyrias (acute intermittent porphyria, variegate porphyria (VP), hereditary coproporphyria (HCP), 5-aminolevulinic acid (ALA) dehydrase deficiency, and porphyria cutanea tarda), the liver is the major, if not sole, site of expression of the biochemical abnormality. In protoporphyria and hepatoerythropoietic porphyria, both the liver and the bone marrow contribute to the biochemical abnormality. This review will briefly delineate the mechanisms by which hepatic biochemical abnormalities occur in the porphyrias. It will also discuss the manner in which liver damage occurs in these disorders, particularly in porphyria cutanea tarda and protoporphyria.

Reversible cholestatic hepatitis caused by acetohexamide

We report a case of cholestatic hepatitis accompanied by peripheral and hepatic eosinophilia in a patient taking acetohexamide for a period of 1.5 yr. Jaundice developed acutely and was accompanied by fever. After discontinuation of the drug, there was no evidence of further damage, with prompt normalization of liver enzymes, bilirubin, and eosinophil count.