Effects of calcium antagonist diltiazem on liver calcium content and necrosis of hepatocytes in rats following treatment with CCL4.

To study the relationship between the changes in hepatocytes and calcium contents in the liver of 42 rats treated with CCl4 and the effect of a calcium antagonist diltiazem on the liver injury, we determined liver calcium content, serum alanine aminotransferase (ALT), and serum levels of triiodothyronine (T3), thyroxine (T4), the T3/T4 ratio, and calcium before and 6 to 72 hr after treatment with a single oral dose of CCl4 (0.5 ml/kg) in 21 rats (Group I) and in 21 rats treated with diltiazem (10 mg/kg) intraperitoneally three times, 24 hr before, simultaneously with, and 24 hr after administration of the same doses of CCl4 (Group II). The maximum calcium content in Group I was 259.7 +/- 53.3 micrograms/g wet weight at 24 hr after treatment, whereas it was 113.0 +/- 51.1 micrograms/g wet weight in Group II, and a significant difference was seen between them (p less than 0.05). The ALT levels in both groups elevated after 18 to 24 hr and a significant difference was also found between the two levels at 24 hr (p less than 0.05). The T3/T4 ratio in Group I decreased immediately, but increased later. The ratio in Group II maintained the level before treatment. Correlation between the calcium content and the grade of centrilobular necrosis was significantly seen in Group I (r = 0.82, p less than 0.001), but was not found in Group II. The grade of centrilobular necrosis appeared to be more severe at 24 to 48 hr in Group I than in Group II.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in liver calcium content in relation to serum triiodothyronine (T3), thyroxine (T4) and T3/T4 ratio in rats treated with CCL4.

To evaluate the relation between liver calcium content and microsomal function in liver injury, we determined liver calcium content, serum triiodothyronine (T3), thyroxine (T4), T3/T4 ratio and serum glutamic pyruvic transaminase (SGPT) content in rats treated with CCl4. The T3/T4 ratio decreased from 1.9 to 1.2 at 6 hr after treatment, but elevated immediately to 3.2 at 36 hr after, and returned to normal at 54 hr after treatment. The calcium content increased from 27 micrograms/g wet weight to 448 micrograms/g wet weight 24 hr after treatment and decreased to normal 78 hr after treatment. The SGPT concentration showed the highest 12 hr after and returned to normal 72 hr after treatment. The calcium content was significantly correlated with T3 (r = -0.5, p less than 0.05). These results suggest that the increase and decrease in liver calcium content are closely related to the decrease and increase in T3 and T3/T4 ratio, respectively.

Serum thyroid hormone, triiodothyronine, thyroxine, and triiodothyronine/thyroxine ratio in patients with fulminant, acute, and chronic hepatitis.

The concentrations of triiodothyronine (T3), thyroxine (T4), T3/T4 ratio, free thyroxine index, and thyroxine-binding globulin were investigated in 114 viral hepatic disease patients and 36 controls. The T3/T4 ratio in healthy hepatitis B virus carriers was significantly greater than those in the controls and fulminant, acute, or chronic active hepatitis patients. The T3/T4 ratio in the fulminant hepatitis patients was significantly less than those in the controls and other liver disease patients. The correlation coefficient between the T3/T4 ratio and microsomal arylamidase activity in liver tissue from 30 patients was 0.78 (p less than 0.001). The correlation coefficient between the T3/T4 ratio and the content of cholinesterase was 0.64 (p less than 0.001). These results suggest that the T3/T4 ratio represents a marker of microsomal function and is useful for estimation of prognosis of fulminant hepatitis or differentiation of various viral hepatic diseases.

Early changes in the levels of serum triiodothyronine (T3), thyroxine (T4), T3/T4 ratio and microsomal carboxylesterase activity in rats following treatment with CCL4.

To study the relationship between the activity of nonspecific carboxylesterase located in the smooth endoplasmic reticulum (SER) of hepatocytes, and serum thyroid hormones including triiodothyronine (T3), thyroxine (T4), and T3/T4 ratio, we determined these hormones, liver carboxylesterase activity, and serum alanine amino-transferase (SGPT) before, and 5 to 720 min after treatment with a single oral dose of CC14 (1 ml/kg) in rats. The serum T3/T4 ratio decreased 5 to 10 min after administration. Each of 16 male and 16 female rats showed a significant correlation between carboxylesterase activity and T3/T4 ratio (male, r = 0.79, p less than 0.01; female, r = 0.84, p less than 0.01), but revealed no correlation between carboxylesterase and T3 or T4, alone. SGPT contents were elevated 6 to 12 h after, whereas T3/T4 ratio decreased gradually during the course. The SER increased mildly 5 min after, but was irregularly distended 6 h after. Changes in the microvilli were not found 5 min after, but the disruption was seen 6 h after. These results suggest that serum T3/T4 ratio is closely correlated with microsomal carboxylesterase activity in CC14-treated rats and represents a microsomal function.

Sodium valproate-induced liver injury.

Centrilobular zonal necrosis developed in the liver of a 37-yr-old woman who had been taking sodium valproate for 1 month as prophylactic anticonvulsant medication after a cranioplasty. A challenge test was positive. Ultrastructurally, the hepatocytes revealed megamitochondria with crystalline inclusions, disorganized rough endoplasmic reticulum, and no increase in smooth endoplasmic reticulum. These findings suggest that cytotoxic liver injury was induced by sodium valproate in our patient.

Nonalcoholic steatohepatitis and cirrhosis with Mallory's hyalin with ultrastructural study of one case.

Clinical features and liver biopsy findings were studied in six patients with nonalcoholic steatohepatitis associated with hyalin. A comparative study was made on the ultrastructure of the hyalin in one patient with nonalcoholic steatohepatitis and in one patient with alcoholic hepatitis. The patients, all over 50 years old, comprised two females and one male with steatohepatitis and three females with micronodular cirrhosis. They showed obesity, hepatomegaly, and mild abnormalities on laboratory tests. Three of them showed maturity-onset diabetes. The hyalin was found in the cytoplasm of swollen hepatocytes of the centrilobular or in the peripheral region of nodules and was accompanied by necrosis. Ultrastructurally, the hyalin comprised filamentous structures and vesicular or angular structures resembling disorganized circular or branched rough endoplasmic reticulum. It resembled that found in the liver of patients with alcoholic hepatitis.

Hydralazine-induced liver injury.

A 68-year-old man developed hepatic injury with no hypersensitivity reaction after three years of hydralazine therapy. The liver injury histologically showed centrilobular zonal necrosis. Clinical, biochemical, and histological recovery followed discontinuation of the drug. Challenge tests and serial liver biopsies revealed that this liver injury was induced by hydralazine.