Zvi Farfel

G-protein diseases furnish a model for the turn-on switch

How does a trimeric G protein on the inside of a cell membrane respond to activation by a transmembrane receptor? G-protein mutations in patients with hypertension and inherited endocrine disorders enhance or block signals from stimulated receptors. In combination with three-dimensional crystal structures and results from biochemical experiments, the phenotypes produced by these mutations suggest a model for the molecular activation mechanism that relays hormonal and sensory signals transmitted by many transmembrane receptors.

Review of echocardiographically diagnosed right heart entrapment of pulmonary emboli-in-transit with emphasis on management

2DE permits detection of thromboemboli transiently entrapped in the right heart chambers while en route to the pulmonary arteries. Review of the 49 cases recorded to date reveals that the supple elongated clot produces a 2DE picture--a mass of changing configuration and striking mobility--that is highly characteristic. Since emboli that become entrapped are large, when managed by medical measures alone they have an attendant mortality rate of 50%, usually soon after 2DE diagnosis, upon completion of pulmonary embolization. Death occurred in 8 of 16 patients treated with anticoagulants, thrombolytic agents, or antiaggregants and in 6 of 13 who received supportive measures only. Of 20 patients referred for surgery (cardiotomy and, in 17, pulmonary embolectomy), only three died, two of them failures of preceding anticoagulant treatment. These data indicate that thromboemboli entrapped in the right heart chambers are best handled as a surgical emergency.

Complex Drug-drug-disease Interactions Between Amiodarone, Warfarin, and the Thyroid Gland

Abstract: Many patients with cardiac arrhythmias require concomitant therapy with warfarin and amiodarone. Beyond the predictable pharmacokinetic drug-drug interaction requiring a significant warfarin dose reduction, the iodine-rich amiodarone affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%-18% of cases. In turn, thyroid disorders may affect warfarin sensitivity, with hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin requirements, respectively. We describe 3 patients on concomitant amiodarone and warfarin who developed amiodarone-induced thyrotoxicosis heralded by a significant decrease in warfarin requirements. We review the literature on the mechanisms of the complex drug-drug and drug-disease interactions within the thyroid gland, warfarin, and amiodarone triad. Given that significant thyroid disorders may be only mildly symptomatic and thus may escape clinical detection, we suggest that thyroid function should be tested in any patient with otherwise unexplained changes in warfarin dose requirements, particularly if concomitantly treated with amiodarone.

Pseudohypoparathyroidism, a Novel Mutation in the βγ-Contact Region of Gsα Impairs Receptor Stimulation

Pseudohypoparathyroidism, type Ia (PHP-Ia), is a dominantly inherited endocrine disorder characterized by resistance to hormones that act by stimulating adenylyl cyclase. It is caused by inheritance of an autosomal mutation that inactivates the α subunit (αs) of Gs, the stimulatory regulator of adenylyl cyclase. In three members of a family, the PHP-Ia phenotype is associated with a mutation (R231H) that substitutes histidine for an arginine at position 231 in αs. We assessed signaling function of αs-WT versus αs-R231H transiently transfected in HEK293 cells. Hormone receptor-dependent stimulation of cAMP accumulation in cells expressing αs-R231H is reduced by ∼75% in comparison to cAMP accumulation in cells expressing αs-WT. A second mutation, αs-R201C, inhibits the GTPase turnoff reaction of αs, thus producing receptor-independent stimulation of cAMP accumulation. The double mutant, αs-R231H/R201C, stimulates cAMP accumulation almost as well (∼80%) as does αs-R201C itself, indicating that the R231H mutation selectively impairs receptor-dependent signaling. In three-dimensional structures of G protein heterotrimers, Arg-231 is located in a region, switch 2, that is thought to interact with the βγ subunit rather than with the hormone receptor. Thus, the R231H phenotype suggests that switch 2 (perhaps in concert with βγ) mediates G protein activation by receptors at a site distant from the receptor-G protein contact surface.

Pseudohypoparathyroidism type 1a presenting as congenital hypothyroidism

PSEUDOHYPOPARATHYROID1SM TYPE 1 is an inherited metabolic disorder characterized by hypocalcemia and hyperphosphatemia, which are caused by end organ resistance to the action of PTH?. 2 Most of these patients have, in addition, the skeletal abnormalities of Albright hereditary osteodystrophy. 2 The molecular basis for the resistance to PTH in most patients ( P H P l a ) is an impairment in c A M P synthesis 3 caused by deficient activity of guanine nucleotide regulatory protein of adenylate cyclase (Nprotein), 4-7 a plasma membrane protein that couples hormone receptors to the catalytic uni t of adenylate cyclase. 8 The localization of the defect distal to the hormone receptor implies that resistance to other hormones that act via c A M P may occur in PHP-1. Indeed, resistance to TSH, glucagon, ADH, and gonadotropins has been demonstrated in patients with PHP-1.6, 7 We describe a child in whom hypothyroidism was diagnosed shortly after birth; at the age of 5 years, a diagnosis of PHP-1 a was made.

Pseudohypoparathyroidism type Ia: two new heterozygous frameshift mutations in exons 5 and 10 of the Gsα gene

Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disease characterized by resistance to PTH and other hormones that act via cAMP. Patients have deficient activity of Gsα, the α subunit of the G protein, which couples hormone receptors to stimulation of adenylate cyclase. We describe two new mutations discovered in two sporadic patients with PHP-Ia. Using genomic DNA, we have amplified exons 2–13 of the Gsα gene (GNAS1) by PCR, and sequenced the resulting products. Both patients had Albrights hereditary osteodystrophy, resistance to multiple hormones, and deficient Gsα activity. In the first patient, a deletion of a C in exon 5 at codon 115 was found. In the second patient, an insertion of a C in exon 10 at codon 267 was detected. Both these heterozygous mutations cause frameshift, and predict decreased production of Gsα. This report adds two new Gsα mutations to the known ten mutations recently described.

Cyclosporine metabolic side effects: association with the WNK4 system

Eur J Clin Invest 2011; 41 (10): 1113–1120

Clopidogrel-induced systemic inflammatory response syndrome

Clopidogrel bisulfate, a widely used inhibitor of platelet aggregation, is considered at least as safe as aspirin. We describe a patient who developed a systemic inflammatory response syndrome consisting of high fever, tachycardia, cellulitis-like rash, impaired liver function, and mild leukopenia after receiving clopidogrel before coronary angiography and stent implantation. The reaction resolved promptly after withdrawal of the drug and recurred shortly after a rechallenge dose was administered, thus making the diagnosis of a clopidogrel-induced reaction highly probable. Recognition of this clopidogrel-induced syndrome is extremely important, both for rapid discontinuation of the offending drug and for avoidance of unnecessary drug therapy or invasive procedures.

Proximal renal tubular acidosis: association with familial normaldosteronemic hyperpotassemia and hypertension.

Further investigation of a family with normaldosteronemic hyperpotassemia and low-renin hypertension showed seven members from three generations, who ranged in age from 4 to 56 years, to be affected. Results of earlier studies had established a normally functioning renin-aldosterone system and normal renal handling of potassium. Constant, albeit mild and asymptomatic, metabolic acidosis in all those affected prompted bicarbonate loading in both the propositus and his brother, which revealed a maximal renal tubular excretory capacity for bicarbonate reabsorption at serum levels of 18 mmole/liter and proved proximal renal tubular acidosis (PRTA). Further, a linear increase in urinary fractional potassium excretion accompanied that of bicarbonate in both, as in normal individuals. Dextrose-insulin infusion in the brother failed to reduce hyperpotassemia. These data support the hypothesis that a generalized cell membrane defect that specifically impedes potassium influx (as opposed to an isolated renal tubular defect) underlies this autosomal dominant disorder.

Adult celiac disease presented with celiac crisis: severe diarrhea, hypokalemia, and acidosis.

An acute severe onset of celiac disease is very uncommon in adults. We describe a patient with adult celiac disease who presented with acute diarrhea that lead rapidly to a life threatening hypokalemia and acidosis, the so-called celiac crisis. Celiac crisis, described mainly in children younger than two years of age, has become very rare due to earlier diagnosis and effective therapy of the disease. The case described is an example of the heterogeneous clinical course of celiac disease and emphasizes the need to consider it in the differential diagnosis, even in adults suffering from acute diarrhea and acidosis.