Dale S. Huff

Veno‐occlusive disease of the liver in children following chemotherapy for acute myelocytic leukemia

Three children developed acute veno‐occlusive disease of the liver following combination chemotherapy for acute myelocytic leukemia. The clinical presentation was similar in all three, with acute onset of hepatomegaly and thrombocytopenia in the absence of significant transaminasemia or icterus. In all three patients, radionuclide imaging with technetium‐99m sulfur colloid showed hepatosplenomegaly, decreased liver uptake, and increased splenic activity. The results of liver biopsy established the diagnosis, revealing marked centrilobular congestion with hemorrhage into the spaces of Disse, atrophy of central hepatic cords, and edema of the walls of the central and sublobular veins. Each patient showed marked improvement following temporary cessation of chemotherapy. The diagnosis of veno‐occlusive disease is suggested by the triad of: (1) clinical signs and symptoms; (2) scintigraphic findings; and (3) temporal relationship to chemotherapy.

Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy (Leigh's Syndrome)

Extract: Proximal renal tubular acidosis has been observed in two infants who had lactic acidosis associated with subacute necrotizing encephalomyelitis. Reduced renal thresholds for bicarbonate (18–19.2 mM/liter) were found in both, in conjunction with the ability to excrete normal quantities of acid. In order to raise the level of serum bicarbonate, increasing rates of infusion of solutions containing bicarbonate were required, because of a progressive increase in serum lactate from 18 to 54 mg/dl. The infusion of sodium bicarbonate expanded the extracellular space, as measured by an increase in chloride space of 12.9%. Volume expansion was associated with a progressive fall in bicarbonate reabsorption from a maximum of 1.91 to 1.02 mM/100 ml glomerular filtration rate. In addition, the tubular reabsorption of phosphate fell from 80 to 60%, urate clearance increased from 8.7 to 20 ml/min/1.73 m2, lactate clearance increased from 0.23 to 22.9 ml/min/1.73 m2, and chloride excretion increased from 0.7 to 3.14 μEq/min/1.73 m2. At autopsy, reduced activity of renal pyruvate carboxylase was demonstrated for the first time in this disease.Speculation: As a reflection of impaired lactate metabolism in subacute necrotizing encephalomyelitis (SNE), generation of ATP may be reduced in the renal cortex. This reduced supply of energy might be expected to impair reabsorption of normal quantities of filtered bicarbonate; proximal renal tubular acidosis may be the result. The fact that other evidence of proximal tubular dysfunction was not observed in the normohydrated state further suggests that failure to reabsorb filtered sodium bicarbonate may be the initial abnormality observed when the supply of energy diminishes in the renal cortex.The changes in the chloride space observed during bicarbonate infusions may provide data useful in the interpretation of changes in the renal threshold both for bicarbonate and for other solutes.Finally, it appears that subacute necrotizing encephalomyelitis may include a spectrum of biochemical abnormalities, and that only certain forms may be associated with renal tubular acidosis.

CYTOMEGALOVIRUS (CMV) CHRONIC INTERSTITIAL PNEUMONITIS IN INFANCY

Although pulmonary involvement in disseminated CMV infection is known, CMV is not a generally recognized cause of interstitial pneumonitis in the absence of infection in other organ systems. Of 16 infants presenting with interstitial pneumonitis during the first 6 months of life, 7 were found to have CMV infection. Other viruses identified were influenza in 2, adenovirus type 5 in one, and parainfluenza type 1 in one, the latter concurrently with CMV infection. None of 5 healthy children with onset of interstitial pneumonitis at 6-42 months of age had CMV infection although influenza was isolated from 2 and adenovirus type 2 from a third child. CMV infection was documented by complement fixing and IgM fluorescent antibodies in all 7 infants, by virus isolation from urine in one, and by the presence of typical CMV-inclusion-bearing cells in lung tissue from the 3 who had biopsy. Lung tissue showed extensive hypertrophy and hyperplasia of type II pneumocytes and mild to severe chronic inflammatory cell infiltrates and interstitial fibrosis. Total serum IgM levels were elevated in 6 infants. The exact time of CMV infection in these 7 infants could not be documented, but was presumed to be after birth, since all were normal through the first weeks of life. Clinical recovery was complete within 6 months in 5 of the 6 followed that long. We conclude that CMV is a major cause of interstitial pneumonitis in young infants.

555 INTRAHEPATIC ALPHA 1-ANTITRYPSIN ACCUMULATION AND Pi TYPE; A CORRELATION STUDY

A retrospective search for propositi to study familial alpha 1-antitrypsin (AAT) deficiency was initiated through an immunohistochemical study of pathological specimens from children with liver disease. A modification of the immunoperoxidase method of Sternberger et al (J. Histochem. Cytochem.18:315, 1970) was used to identify intrahepatic accumulation of AAT, followed by Pityping of the children and/or their parents, using isoelectric focusing, acid starch gel and crossed immunoelectrophoresis.Ten patients with significant AAT accumulation have been Pityped thus far. Four children were PiZZ; four were PiMM. Both groups included children with portal cirrhosis, neonatal hepatitis and/or biliary atresia. Two children with liver lesions resembling tyrosinosis were typed as MZ and M (tentative). Malton An additional child (deceased) is presumed to have been AAT deficient on the basis of serum electrophoresis; his parents are unavailable for typing. The immunohistochemical identification of AAT in MM and non-M individuals suggests that AAT accumulates in damaged livers regardless of the Pi type. The identification of AAT in the liver cannot be considered proof of PiZZ genotype, but must be followed by typing. Supported in part by NlH grants CA 19834 and RR5624.

PULMONARY COMPLICATIONS OF HYPOGAMMAGLOBULTNEMIA

Ten boys with congenital hypogammaglobulinemia from 4 families have been followed for 7-18 years. Five were diagnosed in infancy. Serum IgG was below 1 mg/ml in all but one (2.1 mg/ml after therapy), IgA below 0.05 mg/ml in all and IgM below 0.1 mg/ml in all but one (0.2 mg/ml). All received gammaglobulin from diagnosis and 5 plasma for ½ to 4 years. All had multiple episodes of acute bronchitis and pneumonia beginning early. H.influenzae (non-typeable) and Staph.aureus were the major pathogens, viruses were not found. One child age 10, died of bronchopneumonia and sepsis complicating adrenocorticosteroid treated chronic myositis. He and 3 of the 7 surviving children aged 7, 9 and 13 years, have no definite chronic pulmonary disease, though acute infections were often followed by a persistent cough in spite of intensive antibiotic therapy. This phenomenon led to bronchiectasis in the other 6. Two died of pulmonary insufficiency at ages 15 and 20. Among those surviving with bronchiectasis, 2 have severe restrictive and obstructive patterns in pulmonary function and 3 aged 16-21 had lobectomy. Pathological examination revealed severe bronchiectasis and sclerosis of bronchial arteries. The severity of pulmonary disease could not be correlated with initial serum immunoglobulin levels, proportion of B lymphocytes in peripheral blood, age at onset of gammaglobulin therapy, serum immunoglobulin levels during therapy or antibiotic therapy.