The mechanism of recovery of hepatic T4-5'-deiodinase during glucose-refeeding: role of glucagon and insulin

Refeeding studies were performed on male Sprague-Dawley rats that had been fasted for 72 hours to characterize the specific effect of carbohydrates on T₃ metabolism. Fasting is associated with low serum T₃ levels and reduced hepatic T₄-5′-deiodinase activity (T₄ → T₃). Carbohydrate refeeding (20% glucose in H₂O) normalized both the serum T₃ and hepatic T₄-5′-deiodinase activity within 72 hours, whereas fat (10% Intralipid) and amino acids (5.5% Travasol) had no effect after 72 hours of refeeding. Refeeding with a mixed diet (Purina Rodent Chow) occasionally reactivated hepatic T₄-5′-deiodinase activity, however, normalization of enzyme activity did not occur within 72 hours. Time-course studies demonstrated that hepatic T₄-5′-deiodinase activity was not stimulated until 24 hours of carbohydrate refeeding had elapsed and that 48 to 72 hours were required for normalization. The mechanism of the carbohydrate-refeeding effect was characterized by analyzing the alterations in the kinetics Michaelis constant (Km) and maximal velocity (Vmax) of hepatic T₄-5′-deiodinase and the changes in the hepatic content of nonprotein sulfhydryl groups (NP-SH), which are possible enzyme cofactors. There was no relationship between the hepatic enzyme activity and the NP-SH response during the refeeding period. Moreover, homogenate enrichment with the sulfhydryl compound, dithiothreitol (DTT), did not alter the temporal profile of the enzyme recovery consequent to refeeding. Refeeding with carbohydrate had no effect on the Km of hepatic T₄-5′-deiodinase but had a significant effect on the Vmax. Refeeding with glucose induced an increase in enzyme Vmax over the time-course, which became significant (P < 0.005) compared with the enzyme Vmax of the fasted group by 72 hours. During carbohydrate refeeding, a positive correlation was noted between the ratio of serum insulin to glucagon and hepatic-T₄-5′-deiodinase activity (r = 0.82, P < 0.001), whereas a negative correlation was found between enzyme activity and the ratio of serum glucose to insulin (r = ?0.9, P < 0.001). Furthermore these correlations also applied during refeeding with fat and amino acids. Thus, the carbohydrate-refeeding reactivation of hepatic T₄-5′-deiodinase in fasted rats is a delayed process that requires a refeeding period equivalent to the duration of fasting for enzyme normalization to occur. Recovery was due to an increase in the hepatic content of active enzyme rather than an enhancement of cofactor supply. The glucoregulatory hormones, glucagon and insulin, may modulate these carbohydrate induced changes on hepatic T₄-5′-deiodinase. Moreover, the differential reaction of hepatic T₄-5′-deiodinase to specific nutriments may be mediated by these glucoregulatory hormones.     

Parallel adrenal and renal abnormalities in young patients with essential hypertension

To determine whether the previously described abnormalities in adrenal secretion and renal blood flow in essential hypertension are associated, we examined the responses to the relevant systems in 18 patients with essential hypertension. Young patients, under 30 years of age, were studied to minimize the likelihood that the phenomena were secondary to long-standing hypertension. To achieve a wide span of sodium balance, studies were performed during a high (200 mEq) sodium intake, a restricted (10 mEq) sodium intake and a restricted sodium intake supplemented by a further short-term diuretic-induced volume deficit (furosemide, 180 to 300 mg, to reduce body weight by 1 to 1.5 kg). The indexes measured included cardiac output (indocyanine green indicator dilution), plasma volume (¹²⁵I albumin space), renal blood flow (radioxenon transit), plasma renin activity and aldosterone levels and aldosterone secretory rate. All of these variables, with the exception of Mood pressure and total peripheral resistance, were within the normal range during the two diets. However, the aldosterone secretory response to diureticinduced volume depletion on a low-sodium diet was clearly blunted in nine subjects. These nine subjects (abnormal responders) had a virtually absent aldosterone increment (23 ± 34 μg per 24 hours) compared with the normal responders (502 ± 70 μg per 24 hours). In addition, renal blood flow was significantly higher in these same nine subjects during both a high sodium intake (434 ± 19 versus 342 ± 26 ml/100 g per minute) and a restricted sodium intake (446 ± 11 versus 285 ± 39 ml/100 g per minute). Yet, there were no significant differences between these two groups in sodium or potassium balance, blood pressure, plasma volume, cardiac index or plasma renin activity during a high or low sodium intake. Normally, control of both aldosterone release by the adrenal and renal perfusion is dominated by angiotensin; an apparently blunted response of both systems suggests that there may be a generalized abnormality in the way angiotensin interacts with its target tissues in many young patients with essential hypertension.     

Diagnosis of von Willebrand's disease. A comparative study of diagnostic tests on nine families with von Willebrand's disease and its differential diagnosis from hemophilia and thrombocytopathy.

Nine probands with von Willebrand's disease, and their family members, totalling 43 people, were examined. Twenty-seven had a history of bleeding; 29 had an increased factor VIII activity:factor VIII related antigen ratio; 24 had a decreased factor VIII related antigen; 23 had a prolonged bleeding time; 19 had a reduced platelet adhesiveness; 16 had a decreased factor VIII activity; and 14 had an abnormal ristocetin-induced platelet aggregation. Eight members with both normal beleeding time and normal factor VIII activity were found to have other abnormal tests: elevated ratio of factor VIII activity to factor VIII related antigen in seven; decreased factor VIII related antigen in four; and reduced platelet adhesiveness in one. Therefore, ratio of factor VIII activity to factor VIII related antigen and factor VIII related antigen are more sensitive and may be used for the detection of heterozygous carriers of von Willebrand's disease. Although patients with thrombocytopathy may have a prolonged bleeding time, decreased platelet adhesiveness and reduced platelet aggregation by ristocetin, their factor VIII activity, factor VIII related antigen and ratio of factor VIII activity to factor VIII related antigen are normal and their abnormal ristocetin test cannot be corrected by the addition of factor VIII concentrate. Hemophilic subjects and hemophilic carriers, who are deficient in factor VIII activity, usually have a normal bleeding time, normal platelet adhesiveness, and normal ristocetin test. In contrast to patients with von Willebrand's disease, their factor VIII related antigen is normal or slightly increased and their ratio of factor VIII activity to factor VIII related antigen is significantly reduced. We conclude that ratio of factor VIII activity to factor VIII related antigen and factor VIII related antigen are not only more sensitive but also more specific for the diagnosis of von Willebrand's disease.     

Serologic studies in a family with heterozygous C2 deficiency

Twelve family members of a patient with systemic lupus erythematosus (SLE) and heterozygous deficiency of the second component of complement (C2) were studied. Histocompatibility (HLA) typing was determined for A, B, and DR and MB antigens. Serum samples were tested for a variety of antinuclear antibodies (ANA), lymphocytotoxic antibodies and rheumatoid factors, and C2 levels were determined by hemolytic titration. Inheritance of C2D, the gene coding for C2, was limited to the haplotype HLA-A25, B18, DR2. Low but significant titers of ANA, rheumatoid arthritis nuclear antigen (RANA) and/or rheumatoid factors were found in eight of the nine adult family members without association with HLA haplotype. The sister of the proband had persistently strongly positive LE cell preparations for more than a decade and had joint pains while taking sulfa drugs. The son of the proband had leukemia. All other family members were healthy. We conclude that the increased incidence of rheumatic disease in persons with C2D deficiency is multifactorial and requires environmental factors or other hereditary factors unrelated to the HLA-A25, B18, DR2 haplotype. The C2D gene is clearly not associated with positive ANA tests or immunoprecipitins to RANA.     

Severe depression of high-density lipoprotein cholesterol levels in weight lifters and body builders by self-administered exogenous testosterone and anabolic-androgenic steroids

The effects of nonphysician prescribed, self-obtained, self-administered exogenous anabolic-androgenic steroids and testosterone on plasma total, high- and low-density lipoprotein cholesterol (HDLC, LDLC), and triglycerides were evaluated in 14 adult white men, 11 body builders and 3 power weight lifters. Lipids and lipoprotein cholesterols were quantified during active physical conditioning, both on (for at least 1 month, mean +/- SD 1.8 months) and off (for at least 4 months, 7.3 +/- 2.7 months) self-administered exogenous androgenic steroids. The subjects took 50 to 100 mg methandrostenolone daily plus weekly injections of testosterone 100 to 200 mg and nandrolone decanoate 100 to 200 mg per week. Mean (SD) HDLC on exogenous androgenic steroids, 29 +/- 8 mg/dL, was severely depressed, and was less than 50% of the consistently elevated mean HDLC when exogenous steroids were not used (61 +/- 14 mg/dL, P less than .01 for paired differences). During anabolic steroid use, HDLC was less than or equal to the age- race- and sex-specific 10th percentile in 11 of the 14 men, whereas while off anabolic steroids, HDLC was greater than or equal to the 90th percentile in 7 of the 13 men, and in the top quartile for 3 of the remaining 6 men. Mean LDLC was higher on androgenic steroids (150 +/- 44) than off (125 +/- 38 mg/dL), P less than .05 for paired differences. The ratio of LDLC/HDLC during exogenous steroid use (6.0 +/- 3.7) was nearly triple the ratio obtained when steroids were not taken (2.2 +/- 1.0), P less than .01 for paired differences.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlation of plasma propylthiouracil levels with inhibition of thyroid hormone synthesis in the rat

The inhibition of thyroid hormone synthesis was studied in relation to plasma levels of 6-n-propyl-2-thiouracil (PTU). Na ¹²⁵I (5 μCi) was injected i.p. into adult male Sprague-Dawley rats. After 30 min, graded doses of PTU (0.2 mg/kg, 0.1 mg/kg, and 0.05 mg/kg) were similarly injected. Thyroid hormone synthesis was followed by the accumulation of radioactivity into thyroid glands, which were removed at specified time intervals. PTU levels were measured spectrophotometrically at the time of sacrifice. Additionally, PTU (³⁵S) was used to confirm blood levels of PTU and also to follow intrathyroidal PTU levels. Plasma PTU levels in excess of 0.18 μg/ml completely inhibited thyroid hormone synthesis. Levels between 0.14 and 0.09 μg/ml had a partial effect, and PTU levels less than 0.09 μg/ml had no effect on thyroid hormone synthesis.     

Strychnine poisoning. Recovery from profound lactic acidosis, hyperthermia, and rhabdomyolysis

Strychnine poisoning results in a predictable and treatable sequence of events involving blockade of the inhibitory neurotransmitter, extensor muscle spasms, seizures, and respiratory paralysis. These spasms may lead to hyperthermia, profound lactic acidosis, and rhabdomyolysis. Acidosis is primarily attributable to lactate, as indicated by the correlation between arterial pH and log of lactic acid concentration (r = -0.878). Interruption of the strychnine blockade is the primary therapy for strychnine poisoning. Phenobarbital in moderate doses should be the first intervention and anesthetic doses should be used if necessary. Suppression of convulsions will permit successful management of the complications of strychnine poisoning. Our patient survived, even though at one point he had a pH of 6.55, a lactate level of 32 mM/liter, a temperature of 43 degrees C, and rhabdomyolysis with an increased creatine phosphokinase level of 359,000 mU/ml (5,983 mumol/s/liter).     

Serum high density lipoprotein cholesterol correlates with presence but not severity of coronary artery disease

An elevated serum level of low density lipoprotein (LDL) is a risk factor for the development of coronary artery disease, whereas elevated levels of high density lipoprotein (HDL) appear to have a protective effect, and the total cholesterol to HDL ratio has been suggested as an improved method for assessing risk. We determined cholesterol, HDL and triglycerides in 189 patients undergoing diagnostic cardiac catheterization to determine if these variables correlate with the severity of coronary artery disease assessed as the number of major coronary vessels having ≥ 70 percent stenosis. HDL was higher in the group with zero vessel disease (54 ± 2.3 mg/dl ± SEM) than in those with one, two or three vessel disease (43 ± 1.8, 45 ± 1.8 and 51 ± 1.2, respectively), and the cholesterol to HDL ratio was lower in the group with zero vessel disease (4.1 ± 0.2 compared to 6.1 ± 0.3, 5.7 ± 0.2 and 6.4 ± 0.3 in the groups with 1, 2 and 3 vessel disease).Using analysis of variance, patients with no coronary artery disease (zero vessel disease) differed from those with coronary artery disease in HDL (p < 0.005), triglycerides (p > 0.01), cholesterol (p < 0.005) and cholesterol to HDL (p > 0.005), but no significant differences were found between patients with coronary artery disease and a different number of vessels involved. There were no significant differences between the groups in age, and although the group with zero vessel disease had more females than the others, there were no differences in cholesterol, HDL, cholesterol to HDL ratio, or triglycerides between male and female patients with no coronary artery disease. We conclude that the cholesterol to HDL ratio correlates with the presence but not severity of coronary artery disease.     

Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome: Report of two cases and review of the literature

Cushing's syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushing's syndrome, we recommend repeated ACTH measurement and selective venous sampling—particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.     

Plasma lipoprotein abnormalities associated with acquired hepatic triglyceride lipase deficiency

Two enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are released into human plasma after intravenous injection of heparin. LPL is the major enzyme responsible for initiating catabolism of chylomicrons and very-low-density lipoproteins (VLDL). The physiological role of HTGL is less certain. HTGL has been postulated to be an alternate enzyme to LPL in hydrolysis of triglyceride in VLDL and to be an important enzyme for removal of phospholipid from both low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In this latter role, this enzyme would convert larger, lighter lipoprotein particles to smaller denser particles. HTGL deficiency has been found in severe liver disease and with a genetic deficiency of this enzyme. A unique patient is described with acquired hepatic triglyceride lipase deficiency and vitamin A intoxication. This patient developed hypercholesterolemia with an increase in both LDL and HDL. An increased proportion of lighter LDL (LDL1) and HDL (HDL2) was noted. In addition, after administration of heparin there was no shift in the distribution of apoE in plasma fractionated using a column containing 4% agarose. These findings are consistent with a postulated role of HTGL in metabolism of light LDL and HDL particles and some classes of apoE containing lipoproteins.