Acta med. scand. Vol. 199, pp. 345-348, 1976
Liver Biopsies in Epileptics during Anticonvulsant Therapy Niels Otto Jacobsen, Leif Mosekilde, 0. Myhre-Jensen, Ejner Pedersen and K. E. Wildenhoff From the Department of Neurology, Arhus Kommunehospital, and the University Institute of Pathology, Arhus Amtssygehus, Arhus, Denmark
ABSTRACT. Liver function tests, performed in 11 epileptics under antiepileptic treatment for 10-35 years, showeda slight increasein serumalanine aminotransferasein six patientsand a marked increased level of serum alkaline phosphatases in four. Liver biopsies revealed few uni- or paucicellular necroses in five patients. Granulomatous hepatitis was found in one patient in whom sarcoidosis was later diagnosed. None of the biopsies showed signs of permanent liver damage.
In diphenylhydantoin (DPH) treatment, hypersensitivity hepatitis is a well known phenomenon presenting itself a few weeks after the institution of drug administration (10). Otherwise, hepatotoxicity of DPH is undocumented. However, the findings of increased serum alkaline phosphatase activity (both liver and bone isoenzymes) (1, 9, 18) and serum alanine aminotransferase activity (1) could be an indication of liver damage in patients during long-term DPH therapy. In the present investigation, hepatological studies including liver biopsies were performed to elucidate this problem. PATIENTS AND METHODS Eleven epileptics under antiepileptic treatment for 10-35 years were investigated. Their age and sex distribution and the duration ofantiepileptic treatment are shown in Table I. The patients had no symptoms or clinical signs of liver disease, and apart from anticonvulsant drugs none of them received any medication. All epileptics received DPH, the mean total dose being 1 115 g (range 236-2 022). Three epileptics (nos. 2 , 7 , 9 ) had been treated only with DPH; the others had received DPH in combination with one or more of the following drugs: phenobarbitone, primidone, and carbamazepine.
Determinations of serum bilirubin ( 7 ) , serum alanine aminotransferase (3), serum aspartate aminotransferase (3), serum alkaline phosphatase (3), plasma prothrombin time (16) and serum albumin (20) were performed together with the bromsulphalein (BSP) retention test (23). Needle biopsy of the liver was performed by the method of Menghini. The specimens obtained were fixed in neutral phosphate-buffered 4 % formaldehyde. Paraffin sections were stained with hematoxylin-eosin, Van Gieson, trichromeMasson, PAS, and Gordon and Sweet’s reticulin stain. Sections from all biopsies were assessed independently by two observers and then reassessed jointly.
RESULTS The results of the biochemical tests are shown in Table I. Serum aspartate aminotransferase was essentially normal in all patients, while serum alanine aminotransferase was slightly increased i n six and serum alkaline phosphatases markedly increased in four patients. All patients had normal serum bilirubin and normal plasma prothrombin time. In one patient the albumin concentration in serum was below normal. The BSP retention test was normal in all patients. The histological observations in the 1 1 biopsies are summarized in Table 11. One biopsy (no. 1) showed sarcoid granulomata and moderate lymphocyte infiltration in the portal spaces. This biopsy specimen also contained a few focal necroses in the parenchyma, and focal lymphocyte infiltrations as well as focal proliferations of Kupffer cells were seen in the lobules. Further investigations have shown additional signs of sarcoidosis, and all inflammatory changes observed in the biopsy specimen may be Acta med. scand.
199
346
N . 0 .Jacobsen et al.
Table I . Clinical, biochemical and morphological data in 11 epileptic patients during long-Ierm nnficonvulsant therapy
Pat. no. 1
2 3 4 5 6 7 8 9 10 11 Normal rangeb
Age (y.) 19 21 22 21 23 22 18 50 25 27 34
Duration of treatment Sex
(y.)
0 0 0 0 6 6 6
11
d
d 6
35 20 I1
6
15
14 10 10
14 13 11
S-alanine aminotransferase (Ull)
S-aspartate aminotransferase (U/I)
S-alkaline S-biliphosrubin phatase (mgl (Ull) 100 ml)
I2 18 12 44 41 31 25 29 36 17 46
13 14 16 29 26 25 26 25 24 18 28
435 115 109 184 282 389 47 1 I46 178 117 171
9-25
5-25
105-190 0.3-1.1
0.5 0.6 0.7 0.6 0.6 0.1 0.1 0.6 0.5 0.8 0.6
P-prothrombin time (9%) 71
loo70 71
68 70 89 68 81 62 7s 50-100
S-albumin
(dl) 34.1 32.4 34.4 40. I 34.0 38.7 43.5 26.8 35.6 37.7 31.4
30.1-42.5
BSP (%)
2 2 5 3 7 7 3 2 6 3 6
Liver biopsy" a, b , c . d a
a
a a a
Liver Biopsies in Epileptics during Anticonvulsant Therapy Niels Otto Jacobsen, Leif Mosekilde, 0. Myhre-Jensen, Ejner Pedersen and K. E. Wildenhoff From the Department of Neurology, Arhus Kommunehospital, and the University Institute of Pathology, Arhus Amtssygehus, Arhus, Denmark
ABSTRACT. Liver function tests, performed in 11 epileptics under antiepileptic treatment for 10-35 years, showeda slight increasein serumalanine aminotransferasein six patientsand a marked increased level of serum alkaline phosphatases in four. Liver biopsies revealed few uni- or paucicellular necroses in five patients. Granulomatous hepatitis was found in one patient in whom sarcoidosis was later diagnosed. None of the biopsies showed signs of permanent liver damage.
In diphenylhydantoin (DPH) treatment, hypersensitivity hepatitis is a well known phenomenon presenting itself a few weeks after the institution of drug administration (10). Otherwise, hepatotoxicity of DPH is undocumented. However, the findings of increased serum alkaline phosphatase activity (both liver and bone isoenzymes) (1, 9, 18) and serum alanine aminotransferase activity (1) could be an indication of liver damage in patients during long-term DPH therapy. In the present investigation, hepatological studies including liver biopsies were performed to elucidate this problem. PATIENTS AND METHODS Eleven epileptics under antiepileptic treatment for 10-35 years were investigated. Their age and sex distribution and the duration ofantiepileptic treatment are shown in Table I. The patients had no symptoms or clinical signs of liver disease, and apart from anticonvulsant drugs none of them received any medication. All epileptics received DPH, the mean total dose being 1 115 g (range 236-2 022). Three epileptics (nos. 2 , 7 , 9 ) had been treated only with DPH; the others had received DPH in combination with one or more of the following drugs: phenobarbitone, primidone, and carbamazepine.
Determinations of serum bilirubin ( 7 ) , serum alanine aminotransferase (3), serum aspartate aminotransferase (3), serum alkaline phosphatase (3), plasma prothrombin time (16) and serum albumin (20) were performed together with the bromsulphalein (BSP) retention test (23). Needle biopsy of the liver was performed by the method of Menghini. The specimens obtained were fixed in neutral phosphate-buffered 4 % formaldehyde. Paraffin sections were stained with hematoxylin-eosin, Van Gieson, trichromeMasson, PAS, and Gordon and Sweet’s reticulin stain. Sections from all biopsies were assessed independently by two observers and then reassessed jointly.
RESULTS The results of the biochemical tests are shown in Table I. Serum aspartate aminotransferase was essentially normal in all patients, while serum alanine aminotransferase was slightly increased i n six and serum alkaline phosphatases markedly increased in four patients. All patients had normal serum bilirubin and normal plasma prothrombin time. In one patient the albumin concentration in serum was below normal. The BSP retention test was normal in all patients. The histological observations in the 1 1 biopsies are summarized in Table 11. One biopsy (no. 1) showed sarcoid granulomata and moderate lymphocyte infiltration in the portal spaces. This biopsy specimen also contained a few focal necroses in the parenchyma, and focal lymphocyte infiltrations as well as focal proliferations of Kupffer cells were seen in the lobules. Further investigations have shown additional signs of sarcoidosis, and all inflammatory changes observed in the biopsy specimen may be Acta med. scand.
199
346
N . 0 .Jacobsen et al.
Table I . Clinical, biochemical and morphological data in 11 epileptic patients during long-Ierm nnficonvulsant therapy
Pat. no. 1
2 3 4 5 6 7 8 9 10 11 Normal rangeb
Age (y.) 19 21 22 21 23 22 18 50 25 27 34
Duration of treatment Sex
(y.)
0 0 0 0 6 6 6
11
d
d 6
35 20 I1
6
15
14 10 10
14 13 11
S-alanine aminotransferase (Ull)
S-aspartate aminotransferase (U/I)
S-alkaline S-biliphosrubin phatase (mgl (Ull) 100 ml)
I2 18 12 44 41 31 25 29 36 17 46
13 14 16 29 26 25 26 25 24 18 28
435 115 109 184 282 389 47 1 I46 178 117 171
9-25
5-25
105-190 0.3-1.1
0.5 0.6 0.7 0.6 0.6 0.1 0.1 0.6 0.5 0.8 0.6
P-prothrombin time (9%) 71
loo70 71
68 70 89 68 81 62 7s 50-100
S-albumin
(dl) 34.1 32.4 34.4 40. I 34.0 38.7 43.5 26.8 35.6 37.7 31.4
30.1-42.5
BSP (%)
2 2 5 3 7 7 3 2 6 3 6
Liver biopsy" a, b , c . d a
a
a a a
