Reversibility of Extensive Liver Damage in Galactosemia

GASTROENTEROLOGY 69:496- 502, 1975 Copyright© 1975 by The Williams & Wilkins Co.

Vol. 69, No . 2

Printed in U.S.A.

REVERSIBILITY OF EXTENSIVE LIVER DAMAGE IN GALACTOSEMIA MICHAEL

N.

APPLEBA UM, M . D ., AND M. MICHAEL THALER, M .D.

Univ ersity of California , San Francisco , Departm ent of Pediatrics, San Francisco, California

An infant with galactosemia is reported in whom extensive liver damage developed by 1 month of age. Liver biopsy obtained prior to treatment indicated extensive periportal and intralobular fibrosis, ductular dysplasia, " pseudoglandular" transformation, and distortion of periportal vasculature. Three months after institution of a galactosefree diet, clinical and biological evidence of liver disease disappeared, and follow-up biopsy at 5 months of age showed normal hepatic histology. These findings demonstrate that functional and histological abnormalities consistent with cirrhosis can be completely reversed by dietary management in galactosemia . Transferase galactosemia is an autosomal recessive genetic disorder due to deficiency of galactose-1-phosphate uridyltransferase, the enzyme which converts galactose to glucose. 1 Infants with galactosemia who are maintained on a standard milk diet, develop vomiting, diarrhea, cholestatic jaundice, and failure to thrive because of the toxic effects of galactose derived from lactose in milk. Hepatotoxicity develops rapidly during the first few weeks after birth, and portal hypertension is usually present by 6 months of age in milk-fed galactosemic infants. 2 Liver disease progresses relentlessly in such babies and is responsible for most of the mortality in galactosemia. The incidence of persistent liver disease in children who are treated for galactosemia is unknown, but clinical signs of liver disease tend to disappear in galactosemic babies on a galactose-free diet. z-s The effectiveness of dietary therapy in resolving liver parenchymal lesions in galactosemia is less clear. We are reporting complete recovery of normal hepatic histolReceived November 1, 1974. Accepted February 25, 1975. Address requests for reprints to: Michael N . Applebaum, M.D ., Univers ity of California, San Fran cisco, Department of Pediatrics, 3rd Avenue and Parnass us Street, San Francisco, California 94143.

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ogy after advanced and severe liver damage had become established in a young infant with galactosemia. This result, and concurrent return to normal clinical status and liver function, was achieved following 3 months on a galactose-free diet.

Case Report K. G. , a white female, was admitted to the University of California Hospital, San Francisco, at 28 days of age for evaluation of failure to thrive, jaundice, and hepatomegaly. She was the second child of healthy young parents and weighed 4.0 kg at birth. The family history was significant in that the patient's only sibling had died with severe dehydration at 1 month of age, having been jaundiced since birth , with poor feeding and failure to thrive. Autopsy at another center was described as showing "portal fibrosis ," but a specific diagnosis was not made . Review of sections taken at autopsy was not possible. Feeding with a standard milk formula was started during the first 24 hr after birth. Vomiting began after several days on the formula, and the infant became progressively more irritable . By 2 weeks of age weight loss was nearly 1 kg. Jaundice with hepatomegaly were noted at 1 month , and a non-glucose reducing substance was detected in urine. Physical examination on admission revealed mild scleral icterus, posterior subcapsular cataracts , protuberant abdomen with prominent abdominal veins, and a firm liver which ex-

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TABLE I --------..,-----.------~--

Age

--- -- - ----~ --

Prothrombin time

Hemoglobin ·----

First admission Second admission -

months

ii/100 cc

1

12 .6 11.4

6

s<;O'l'

Alkaline ph<)sphatasc

Biliruhin total/ dirert

LDH

Alhumin

·-- ·----- --· l}(J

of normal

/U

Ill

lll!i/IOOm/

Ill

ii/IIHJ <"<"

75

140 :~8

262 2:l2

G.6n.4 0.4/0.2

700 220

:u

[()()

- - - - - -- --'------ -- - - -- --- - -

tended to the midline and was palpable 4 em below the right costal margin. The spleen was not palpable . Neurological status was evaluated as normal. Pertinent laboratory results included conjugated hyperbilirubinemia, elevated transaminase and alkaline phosphatase, and prolonged prothrombin time (table 1). Galactosemia was confirmed when galactose !-phosphate uridyltransferase activity was found to be absent in red blood cells . A percutaneous liver biopsy was obtained, which showed profound distortion of the hepatic architecture with extensive fibrous tissue which invaded the lobular interior, and formed bridges between adjacent portal areas (fig. 1). Portal zones contained dysplastic ductular structures without lumina, occasional bile ducts, and collapsed portal veins (fig. 2). The sinusoidal cords were distorted, irregular, and lined with hyperplastic Kupffer cells. The liver cells were frequently arranged in acinar formations around a central space which was usually filled by a bile plug (pseudoglandular transformation) . Most cells contained prominent fatty deposits and inspissated bile. Several hepatocytes with two or more nuclei were also observed. The infant was treated with a lactose-free diet as soon as the diagnosis was suspected. Symptoms disappeared within a few days, and the jaundice was no longer detectable after :3 weeks. When re-examined 3 months la ter, she was asymptomatic and normally developed. Height and weight were at the 40th percentile. There was no evidence of jaundice or hepatomegaly , but small "oil droplet" cataracts were still present bilaterally. Liver function tests were within normal limits (table 1). Percutaneous liver biopsy at 5 months of age revealed no evidence of fibrosis, fatty change, or lobular disarray and was interpreted as normal (figs . :l and 4) . This second biopsy was only 6 mm in length but included two normal appearing liver lobules. We feel it is unlikely this biopsy represents a regenerative nodule. The medical indications for the initial and repeat biopsy were carefully explained to the parents and after their informed consent the procedures were performed.

'1.7

Discussion The clinical course in this infant with galactosemia was typical of the disease. Approximately 50% of patients present with vomiting and weight loss, 70'};, with hepatomegaly , and 60% with jaundice .~ Posterior subcapsular cataracts have heen noted at birth and appear in GO% of infants before 6 months of age. Liver disease in galactosemia appears to be a major problem in very young infants. A clinical study of 4G cases, including a group on poorly controlled or galactosecontaining diets, indicated that 40% died in the first 6 months after birth with complications of cirrhosis and I H% of the survivors had persistent hepatomegaly .'' Prognosis seems to have improved considerably during the last 10 years,"· 6 which suggests that treatment with a strict galactose-free diet may alter the course of liver disease. One of the earliest reports documenting cirrhosis in galactosemia contained the suggestion that this type of advanced liver disease may he reversible with appropriat.e manageme~t, but direct evidence in support of this possibility was not presented." Smetana and Olen" reached the opposite conclusion from a more extensive examination of liver pathology in galact.osernia. These authors envisioned three stages of development of liver disease: (I) f<1tty metamorphosis, (2) pseudoglnndular transformation, and (:l) portal cirrhosis with regenerative nodules. The findings associated with prefibrotic lesions appeared entirely reversible with therapy, whereas portal fibrosis and nodules were interpreted as irreversible. Hepatic histology in our patient was representative of all three stages. Medline and Medline" in a recent report described the early st rudural

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FIG. 1. Reticulin stain of first liver biopsy showing small nodules and extensive disarray of liver cords ( x 40).

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FIG. 2. Higher magnification of portal area showing distortion of sinusoids by copious fibrous tissue, and dysplasia of bile ducts. Abnormal vascular structures at lower left (terminal arterioles with thickened endothelium, compressed portal venuli); "pseudogland" with bile plug at upper right (Masson's trichrome, x 250).

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FIG. 3. Reticulin sta in of second liver biopsy showing regular appearance of liver cords and absence of nodule formation ( x 40).

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changes in the liver and commented on the progression from severe fatty change to bile ductular proliferation that ultimately leads to fibrosis and cirrhosis. They support the notion that fatty change is clearly reversible but did not comment on the reversibil ity of ductular proliferation . The observations presented in this case report establish that reversibility of extensive hepatic fibrosis, morphologically resembling those observed in frank cirrhosis, can occur in galactosemia. Liver damage in this disease seems to be related to intracellular accumulation of galactose !-phosphate, as patients with galactokinase deficiency do not develop liver damage. This may explain the rapid disappearance of advanced pathology upon removal of the precursor, galactose . Whether this potential for regenerative repair is restricted to liver in infants is unknown. Survival with galactosemia in early infancy appears to depend on hepatic injury, rather than on the neurological manifestations of the disorder. The dangers of delay in treatment, as well as the efficacy of dietary management, are clearly illustrated by the family presented here . Whereas the untreated newborn died with liver disease at 1 month of age, the treated infant recovered completely from extensive livzr damage which had developed after 1

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month on a regular milk diet. These findings suggest that early diagnosis and immediate exclusion of galactose from the diet can bring about complete recovery from life-threatening liver disease in infants with galactosemia. REFERENCES 1. Isselbacher KJ , Anderson EP, Kurahashi K , eta!:

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Congenital galactosemia, a singl e enzymatic block in galactose metabolism . Science 123:635-636, 1956 Hsia DY, Walker, FA : Variability in the clinical manifestations of galactosemia. J Pediatr 59:872-883, 1961 Donnell GN, Collado M, Koch R: Growth and development of children with galactosemia. J Pediatr 58:836-844, 1961 Komrower GM, Lee DH: Long-term follow-up of galactosemia. Arch Dis Child 45:367-373 , 1970 Brandt NJ, Tolstrup N: Problems in the diagnosis of hereditary galactosemia. Acta Pediat Scand 56:85-96, 1967 Smetana HF, Olen E: Hereditary gal actose disease. Am J Clin Pathol 38:3- 25, 1962 Donnell GN, Bergren WR, Perry G, et a l: Galactose-1-phosphate in ga lactosemia. Pediatrics 31 :802-8 10, 1963 Townsend EH, Mason HH, Strong PS : Galactosemia and its relat ion to Laennec's cirrhosis. Pediatrics 7:760- 773, 1951 Medline A, Medline NH: Galactosemia: Early structural changes in the li ver. Can Med Assoc J 107:877-878, 1972