Low Serum T3 and Raised Reverse T3 Levels in Hepatic Cirrhosis: Role of Glucagon

Hepatic parenchymal tissue is known to be one of the major sites of thyroid hormone metabolism as well as glucagon action. Alterations in circulating thyroid hormone concentrations, as well as hyperglucagonemia, are well documented in subjects with hepatic cirrhosis and advanced liver dysfunction. Also, we have documented recently that hyperglucagonemia induced in normal subjects alters thyroid hormone metabolism, with lowering of serum T3 and a rise in serum reverse T3 (rT3) levels. Thus, it is conceivable that rising glucagon concentrations are responsible for altered thyroid hormone levels in hepatic cirrhosis. To examine this hypothesis, this study determined relationships between plasma glucose, glucagon, insulin, and insulin:glucagon ratio on one hand, and thyroid hormone concentrations on the other, in 51 subjects with hepatic cirrhosis. Significant negative correlations were noted between plasma glucagon and serum T3 (r = -0.418, p less than 0.001) as well as T3:T4 ratio (r = -0.627, p less than 0.0001), whereas significant positive correlations were observed between plasma glucagon and serum rT3 (r = 0.504, p less than 0.001) as well as rT3:T4 ratio (r = 0.644, p less than 0.0001). No such significant relationships were noted between either insulin, glucose and insulin:glucagon ratio on one hand and any of thyroid hormone indices on the other. Therefore, this study indicates that, in hepatic cirrhosis, circulating glucagon concentrations may play a major contributing role in induction of altered serum thyroid hormone concentration by influencing thyroid hormone metabolism.     

T4 Thyrotoxicosis with Normal or Low Serum T3 Concentration

Summary: : T₄ thyrotoxicosis with normal or low serum T₃ concentration. A. Joasoo, Aust. N.Z. J. Med , 1975, 5, pp. 432–434.     

Serum T3 and Reverse T3 Levels in Hepatic Cirrhosis: Relation to Hepatocellular Damage and Normalization on Improvement in Liver Dysfunction

Liver is one of the major sites of T4 metabolism. Several studies have reported low serum T3 concentrations and elevated reverse T3 (rT3) levels in hepatic cirrhosis. This study examined the influence of degree of the hepatocellular damage and the effect of improvement in clinical state on thyroid hormone concentrations in 44 cirrhotic patients. Low serum T4 and T3 as well as raised rT3 were observed in cirrhotic patients with advanced liver dysfunction alone. T3 resin uptake was increased in some of these patients suggesting decrease in serum thyroid-binding globulin concentration. In patients with histological changes but with normal liver function tests, serum T4, T3, and rT3 were not altered. Serum T3 and rT3 correlated significantly with liver function tests. T4, T3, and rT3 normalized on improvement in clinical status and liver function tests. Lowest levels of T4 and T3 with extremely high rT3 were seen in patients with extremely advanced liver dysfunction. In these patients, the mortality was high. Therefore, in hepatic cirrhosis, 1) T4 metabolism is altered with lowering of T4 and T3 and a rise in rT3. 2) These changes may be dependent on the degree of hepatocellular damage and reverse on improvement in liver function. 3) T4, T3, and rT3 levels are useful prognostic indices.     

β-Blockers in Hypertension: A Reassessment of the Benefit of Combined α-/β-Blockade

β-Blockers have a long history of use in patients with high blood pressure, either alone or in combination with other classes of antihypertensive agents. Although β-blockers can lower blood pressure effectively, they have not been convincingly shown to reduce the likelihood of some cardiovascular complications from hypertension, and their utility for this purpose has been critically questioned of late. This growing distrust of β-blocker therapy, however, is misguided. Negative sentiments about one drug in a class, as has been the case for atenolol, often become unfairly disparaging of all drugs in a class. In the process of such lumping, the heterogeneity of the various compounds making up a drug class is often neglected. Such is the case for combined α-/β-blockade, which is to be distinguished from β-blockade alone because of differences in hemodynamic and metabolic effects. This should prompt a reappraisal of the role of selected agents, such as the combined α-/β-blocker carvedilol, in the long-term treatment of hypertension.     

β2 glycoprotein-I antigen is increased in primary hyperlipidaemia

Summary. In order to determine whether elevated levels of β₂ glycoprotein-I (β₂GPI) are associated with increased plasma lipids, we measured plasma β₂ GPI antigen levels in 47 patients with primary hyperlipidaemia (20 severe hypercholesterolaemia, nine severe hypertriglyceridaemia, and 18 mixed hyperlipidaemia) and 34 normal healthy subjects. Mean β₂GPI levels were significantly increased in each patient group (302.3, 272.9 and 299.1 mg/1. respectively) compared to controls (199.6 mg/1) (p<0.01). Significant correlations were demonstrated between β₂GPI levels and triglyceride and total cholesterol levels in the control group (r = 0.387, r =0.559: P<0.5), but were not observed in all patient groups. These results indicate that β₂GPI is increased in hyperlipidaemia and that its distribution between plasma lipid fractions is perturbed. Plasma lipid levels should therfore be considered when interpreting results of β₂GPI antigen assays.     

Haemoglobin Inkster (α285 aspartic acid → valineβ2) Coexisting with β-Thalassaemia in a Caucasian Family

S ummary . Haemoglobin Inkster, a new α-chain variant, was discovered in a family which also had the gene for β-thalassaemia. The amino acid abnormality was in αTp-9 which contains 29 amino-acid residues. Structural studies were facilitated by cleavage of the abnormal α-chains with cyanogen bromide followed by tryptic digestion. The substitution was shown to be valine for aspartic acid at position 85 in the α-chain. Affected individuals had no haematological abnormalities. Individuals with both β-thalassaemia and Hb Inkster had slightly lower percentages of Hb Inkster than those found in persons heterozygous for the Hb Inkster gene alone. 'Interaction' between thalassaemia and variant haemoglobin genes involving different haemoglobin loci has been reported in another family with β-thalassaemia and an α-chain haemoglobin mutant, as well as in the converse situation of coexisting β-thalassemia and a β-chain haemoglobin mutant. This decrease in the mutant haemoglobin percentage differs from the more common 'interaction' of thalassaemia and mutant haemoglobin genes involving the same haemoglobin locus, in which the mutant haemoglobin percentage is increased. The mechanism for the 'interaction' is unknown, but the presence of an unusually low percentage of a haemoglobin variant should warrant investigation for coexisting thalassaemia involving a different haemoglobin locus.     

Effect of Pinealectomy on Thyroid Hormone (T4 and T3) Levels in Plasma During Annual Reproductive Cycle in the Freshwater Catfish, Clarias batrachus

Thyroxine and triiodothyronine (T3) were measured by radioimmunoassay in serum and thyroid gland of the freshwater teleost Clarias batrachus. Pinealectomy increased the glandular levels of the thyroid hormones but decreased the plasma levels of T4 concomitantly with the increase of T3 levels. Most of the effects of pinealectomy on thyroid hormones were restricted to the gonadal development periods. Pinealectomy has shown no significant impact on thyroid hormones during the other periods of the reproductive cycle. Thus, it appears that the pineal gland is inhibitory to thyroid hormones during gonadal development and maturation.     

Long-term prognostic value of serum β2 microglobulin in myelomatosis

The prognostic value of serum beta 2 microglobulin (s beta 2m) measured at entry, at plateau and at 3-monthly follow-up times has been assessed for patients in the Medical Research Council's 4th and 5th Myelomatosis Trials. Analysis of 1014 patients confirmed the value of presentation s beta 2m of predicting survival in the short term but showed that predictive value was lost for subsequent survival in those patients who had survived for at least 2 years. However, measurements of s beta 2m taken during follow-up were predictive of subsequent survival. The predictive power of these follow-up measurements was very similar to that for the presenting measurement, and again they were only of value in predicting survival in the next 2 years.     

Compartmentalization regulates the interaction between the platelet integrin αIIbβ3 and ICln

The volume-regulating protein, ICln, interacts with the conserved KxGFFKR α-integrin signature motif. ICln is an abundant protein (4455 ± 650 molecules/platelet) found exclusively in the soluble cytosolic fraction of unactivated platelets. In contrast, its binding partner, the platelet integrin α_IIbβ₃, is present in detergent-insoluble fractions associated with membrane and cytoskeleton subcellular localizations. This study investigated factors that regulate the interaction of ICln with α_IIbβ₃ during platelet activation. His-tagged recombinant ICln bound equally to purified α_IIbβ₃ and to integrin from resting or activated platelets. Binding was not affected by direct integrin activation with Mn⁺⁺ or by inhibitors of integrin occupancy (abciximab, RGD). However, the capacity for interaction between integrin and recombinant ICln was slowly downregulated following prolonged platelet activation for >300 s. In parallel, ICln redistributed to membrane and cytoskeletal platelet subcellular fractions. The time-course of this redistribution preceded the downregulation of integrin binding capacity and suggests that only a short window of opportunity exists for ICln interaction with α_IIbβ₃ to occur. Thus, although ICln has the inherent capacity to bind to α_IIbβ₃ regardless of its activation state, it can only do so following platelet activation. Activation-dependent subcellular redistribution of ICln represents a novel, temporally-regulated mechanism for control of integrin function in platelets.     

Renal Metabolism of β2-Microglobulin

beta 2-microglobulin (beta 2M) is a protein of 11,800 daltons which occurs in the plasma of normal individuals at concentrations of approximately 2 microgram/ml. It is presumed to be relatively freely filterable. More than 99% of the filtered beta 2M is taken up by an active reabsorptive mechanism and catabolized by the renal tubule. The data presented here demonstrate that renal extraction is only slightly diminished by complete ureteral obstruction. The renal extraction of beta 2M is greater than can be accounted for by filtration alone. These data indicate that some uptake of beta 2M occurs from the peritubular capillary circulation. The loading of animals with beta 2M is associated with a marked tubular proteinuria suggesting that this protein may play a part in inducing tubular injury.     

Role of the M3 muscarinic acetylcholine receptor in β-cell function and glucose homeostasis

The release of insufficient amounts of insulin in the presence of elevated blood glucose levels is one of the key features of type 2 diabetes. Various lines of evidence indicate that acetylcholine (ACh), the major neurotransmitter of the parasympathetic nervous system, can enhance glucose-stimulated insulin secretion from pancreatic β-cells. Studies with isolated islets prepared from whole body M₃ muscarinic ACh receptor knockout mice showed that cholinergic amplification of glucose-dependent insulin secretion is exclusively mediated by the M₃ muscarinic receptor subtype. To investigate the physiological relevance of this muscarinic pathway, we used Cre/loxP technology to generate mutant mice that lack M₃ receptors only in pancreatic β-cells. These mutant mice displayed impaired glucose tolerance and significantly reduced insulin secretion. In contrast, transgenic mice overexpressing M₃ receptors in pancreatic β-cells showed a pronounced increase in glucose tolerance and insulin secretion and were resistant to diet-induced glucose intolerance and hyperglycaemia. These findings indicate that β-cell M₃ muscarinic receptors are essential for maintaining proper insulin secretion and glucose homeostasis. Moreover, our data suggest that enhancing signalling through β-cell M₃ muscarinic receptors may represent a new avenue in the treatment of glucose intolerance and type 2 diabetes.     

Globin gene mapping in normal Hb A2 types of β-thalassaemia

Globin-gene mapping of DNA from 13 families with normal Hb A₂β-thalassaemia (both type 1 and type 2) failed to detect any difference from normal in their globin-gene arrangement. We conclude that deletions such as those responsible for γβ-thalassaemia or a 'silent' Hb Lepore are not responsible for this type of β-thalassaemia in Greece.     

Comparison of Haematological Features of the β0 and β+ Thalassaemia Traits in Jamaican Negroes

Haematological characteristics have been compared in 29 subjects with heterozygous β⁰ thalassaemia and in 33 subjects with heterozygous β⁺ thalassaemia, identified by the type of sickle cell-β thalassaemia among close relatives, in a Jamaican Negro population. Total haemoglobin, MCV and MCH were significantly lower in the β⁰ type but the level of Hb A₂ was not significantly different. Individual values for MCV, MCH and Hb A₂ in the β⁺ type occasionally overlapped those in the normal population casting doubt on the adequacy of these criteria in identifying all cases of heterozygous β⁺ thalassaemia. The haematological differences are those which would be expected on theoretical grounds. The inability to confidently differentiate the two types of heterozygous β thalassaemia has implications for genetic counselling. The inability to distinguish heterozygous β⁺ thalassaemia from normals on any single haematological index suggests that surveys depending on estimations of Hb A₂ or on MCV alone may have underestimated the prevalence of the β⁺ thalassaemia gene.     

Australian β0-thalassaemia: a high haemoglobin A2β0-thalassaemia due to a 12 kb deletion commencing 5''to the β-globin gene

A large novel deletional beta zero-thalassaemia mutation associated with unusually high levels of haemoglobin A2 in heterozygotes is described in an Australian family. The deletion was characterized by restriction enzyme analysis followed by PCR amplification and sequencing of the breakpoint region. Australian beta zero-thalassaemia extends from 835 basepairs (bp) 5' to the cap site of the beta-globin gene downstream for 12.023 kb. This deletion, similar to previously described deletional beta zero-thalassaemias associated with high Hb A2, removes sequences 5' to the beta-globin gene promoter and emphasizes the functional importance of the 5' beta-globin region in eliciting the unusually high Hb A2 phenotype.     

Human GABA, Receptor αl and α3 Subunits Genes and Alcoholism

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA effects are largely mediated by binding to the postsynaptic GABA_A receptor, causing the opening of an integral chloride-ion channel. The GABA_A antagonists picrotoxin and bicuculline reduce some ethanol-induced behaviors, such as motor impairment, sedation, and hypnosis. The role of this receptor in alcoholism is further supported by effective alleviation of alcohol withdrawal symptoms by GABA_A agonists. To determine the role of the GABA, receptor (GABR) genes in the development of alcoholism, we have used α₁ and α ₃ simple sequence repeat polymorphisms in a sample of unrelated alcoholics, alcoholic probands with both parents, and psychiatrically normal controls. For the GABRα₁ gene, the differences between allele frequencies, when all alleles were compared together, were not significant between total alcoholics, subtypes of alcoholics, and normal controls. However, for GABRα₃, the differences between total alcoholics and normal controls were significant when all alleles were compared together. The differences between subtypes of alcoholics and normal controls were not significant. The results of haplotype relative risk analysis for both genes, GABRα₁ and GABRα₃, were also negative. It is possible that the sample size in the haplotype relative risk is too small to have power to detect the differences in transmitted versus nontransmitted alleles. There is a need for a replication study in a large family sample, that will allow haplotype relative risk or affected sib-pair analysis.     

Significance of β2-Microglobulin in Liver Diseases

Serum levels of beta 2-microglobulin (beta 2-M) were found to be significantly elevated in acute viral hepatitis, chronic persistent or active hepatitis and liver cirrhosis. beta 2-M values were significantly lower in chronic persistent hepatitis than in the three other groups. Serum beta 2-M was normal in 75 asymptomatic carriers of HBsAg. Steroid therapy was followed by reduction of serum beta 2-M levels in 11 cases of chronic active hepatitis. Variations of beta 2-M were independent from that of transaminases, bilirubin and gamma-globulins.     

Prenatal Diagnosis of β Thalassaemia by Fetal Red Cell Enrichment with NH4Cl-NH4HCO3 Differential Lysis of Maternal Cells

S ummary . Prenatal diagnosis with globin chain synthesis analysis on fetal red blood cells concentrated by NH₄Cl-NH₂HCO₃ differential lysis of maternal cells (Ørskov lysis) was carried out in 27 pregnancies at risk for β thalassaemia and one at risk for sickle cell β⁰ thalassaemia. The β/γ globin chain synthesis ratio was also determined after anti-i differential agglutination (12 cases), in almost pure fetal samples (six cases) and by extrapolation (one case). Differential lysis permitted the study of samples drawn by placental aspiration containing as little as 3.2% fetal red blood cells. There was no consistent difference between the β/γ ratios observed after differential lysis and those determined after the use of the other approaches. A presumptive diagnosis of homozygous β thalassaemia was made in nine cases. All but one of these pregnancies was terminated. The absence of β chain synthesis was confirmed by the study of fetal blood after abortion in four cases with suitable samples. Of the remaining pregnancies, six proceeded to term and non-homozygous infants were delivered. The others are still in progress. No fetal loss occurred. ørskov lysis seems to be a very reliable method for prenatal diagnosis of β chain abnormalities. Moreover it can minimize the number and duration of placental aspirations required and thus the risk to the fetus.     

α4β1 integrin-mediated adhesion of CD34+ cells from patients with chronic myeloid leukaemia: influence of IL-3

Interactions between integrins on haemopoietic progenitor cells and their stromal ligands have an important role in the control of haemopoiesis. Growth factors can modulate these interactions (so-called 'inside-out' signalling) resulting in changes in ligand binding activity. We have studied alpha4beta1 integrin-mediated adhesion to the H120 fragment of fibronectin (which contains the strongest alpha4beta1 binding site) in CD34+ cells from patients with chronic myeloid leukaemia (CML) and have determined the effect of IL-3 on the level of adhesion. Compared to normal CD34+ cells isolated from cord blood and peripheral blood progenitor harvests (mean of 61.4 +/- 14.9% of cells attached) the CML CD34+ cells showed reduced levels of adhesion (mean of 41.9 +/- 14.7%, P < 0.05). The effect of 10 ng/ml of IL-3 resulting in reduced adhesion of normal CD34+ cells at 30 min was absent in 6/7 patients with CML. Abnormalities of adhesion to fibronectin may thus be related to IL-3 pathways affected by BCR-ABL. These findings will have implications for understanding the dysregulation of growth and adhesion in CML.