Tiziano Scalvini

Renal Apolipoprotein A-I Amyloidosis: A Rare and Usually Ignored Cause of Hereditary Tubulointerstitial Nephritis

Apolipoprotein A-I amyloidosis is a rare, late-onset, autosomal dominant condition characterized by systemic deposition of amyloid in tissues, the major clinical problems being related to renal, hepatic, and cardiac involvement. Described is the clinical and histologic picture of renal involvement as a result of apolipoprotein A-I amyloidosis in five families of Italian ancestry. In all of the affected family members, the disease was caused by the Leu75Pro heterozygous mutation in exon 4 of apolipoprotein A-I gene, as demonstrated by direct sequencing and RFLP analysis. Immunohistochemistry confirmed that amyloid deposits were specifically stained with an anti-apolipoprotein A-I antibody. The clinical phenotype was mainly characterized by a variable combination of kidney and liver disturbance. The occurrence of renal involvement seemed to be almost universal, although its severity varied greatly ranging from subclinical organ damage to overt, slowly progressive renal dysfunction. The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria. Histology confirmed tubulointerstitial nephritis. Surprising, amyloid was restricted to nonglomerular regions and limited to the renal medulla. This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits. The tubulointerstitial nephritis as a result of hereditary apolipoprotein A-I amyloidosis is a rare disease and a challenging diagnosis to recognize. Patients who present with familial tubulointerstitial nephritis associated with liver disease require a high index of suspicion for apolipoprotein A-I amyloidosis.

Pyridostigmine enhances even if it does not normalize the growth hormone responses to growth hormone-releasing hormone in patients with Cushing's disease.

Subjects with Cushings disease have diminished growth hormone (GH) response to growth hormone-releasing hormone (GHRH). The aim of our study was to investigate the underlying mechanism of this diminished GH response in these patients using pyridostigmine (PD), an acetylcholinesterase inhibitor, which is reported to increase GH secretion by reducing somatostatin tone. Eight subjects with untreated Cushings disease (caused by a pituitary adenoma) and 6 control subjects received GHRH 100 micrograms in 1 ml of saline, as intravenous bolus injection 60 min after (1) placebo (2 tablets, p.o.) or (2) PD (120 mg, p.o.). After GHRH plus placebo, the GH peak (mean +/- SEM) was significantly lower in subjects with Cushings disease (2.4 +/- 0.5 micrograms/l) compared to control subjects (25.1 +/- 1.8 micrograms/l, p less than 0.05). After GHRH plus PD, the GH peak was significantly enhanced both in subjects with Cushings disease (7.1 +/- 2.3 micrograms/l, p less than 0.05) and in control subjects (42.3 +/- 4.3 micrograms/l, p less than 0.05). In patients with Cushings disease, the GH response to GHRH plus PD was lower with respect to the GH response to GHRH alone in normal subjects. We conclude that hypercortisolism may cause a decrease in central cholinergic tone which is in turn hypothesized to be responsible of an enhanced somatostatin release from the hypothalamus. However, other metabolic or central nervous system alterations may act synergistically with hypercortisolism in causing GH inhibition in patients with Cushings disease.

Anabolic steroids purchased on the Internet as a cause of prolonged hypogonadotropic hypogonadism

OBJECTIVE To report a case of hypogonadotropic hypogonadism due to the chronic abuse of anabolic steroids purchased over the Internet. DESIGN Case report. SETTING Endocrinology unit of the University of Brescia. PATIENT(S) A 34-year-old man. INTERVENTION(S) A single dose (100 μg) of triptorelin (triptorelin test). MAIN OUTCOME MEASURE(S) Clinical symptoms, androgen normalization, levels of serum testosterone, follicle-stimulating hormone, and luteinizing hormone. RESULT(S) Within 1 month, the patients serum testosterone was in the normal range, and he reported a return to normal energy and libido. CONCLUSION(S) The World Anti-Doping Code has proved to be a very powerful and effective tool in the harmonization of antidoping efforts worldwide, but it is insufficient to combat this illegal phenomenon. To tackle the serious side effects caused by doping we believe that it is necessary to increase monitoring and adopt severe sanctions, particularly with regard to Internet sites.

Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis.

Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.

Spermatogenic and Steroidogenic Impairment of the Testicle Characterizes the Hereditary Leucine-75-Proline Apolipoprotein A-I Amyloidosis

CONTEXT The leucine-75-proline variant of apolipoprotein A-I leads to a new hereditary systemic amyloidosis involving mostly the liver and kidney. OBJECTIVE The objective of the study was to examine the effects of this amyloidosis on testicular structure and function. DESIGN This was an observational study in which patients with testicular amyloidosis were characterized. SETTING The study was carried out at the Endocrinology Department of Brescia University. PATIENTS OR OTHER PARTICIPANTS Over a 13-yr period, 25 patients were found to be affected by leucine-75-proline apolipoprotein A-I testicular amyloidosis. Thirteen had the testicle as the first or only organ involved (group 1); in 12 testicular damage followed that of other organs (group 2). INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURE Hormone and lipidic profiles, semen analysis, echographic volume of testicles, testicular histology, and genetic analysis were carried out. RESULTS Group 1 patients were younger than those of group 2. In group 1, eight had hypergonadotropic hypogonadism and five were normogonadic with high gonadotropins; in group 2 all subjects were hypogonadic. All men had low high-density lipoprotein values. Group 1 patients were macroorchid, whereas the testicular volume was at the highest limit in group 2 (group 1 vs. group 2, P < 0.05). All men in the first group and six in the second group were azoospermic; the remaining had oligoposia. Biopsies showed the germinal epithelium replaced by amyloid. Leydig cells were essentially preserved in normogonadic but not hypogonadic patients. CONCLUSIONS This amyloidosis may determine infertility, macroorchidism, and hypogonadism. Endocrine impairment follows spermatogenic impairment.

Effects of fish oil on serum lipids and lipoprotein(a) levels in heterozygous familial hypercholesterolemia

Abstract Ten patients (mean age, 49 ± 14 years) with heterozygous familial hypercholesterolemia who had high levels of lipoprotein (Lp)(a) (>30 mg/dl) and were receiving chronic treatment with simvastatin were treated with six capsules a day of fish oil for 4 weeks. Each 1-gm fish oil capsule contained almost 850 mg of omega-3 fatty acids with a ratio of eicosapentaenoic acid:docosahexaenoic acid of 1:1; the total daily dosage of omega-3 fatty acid was 5.1 gm/day. After 2 and 4 weeks of fish oil supplementation, mean serum Lp(a) levels did not change significantly (baseline, 67 ± 29 mg/dl; week 2, 68.3 ± 35 mg/dl; week 4, 60.6 ± 26 mg/dl). Triglyceride levels decreased by 23% after 2 weeks (from 1.355 ± 0.38 mmol/L to 1.05 ± 0.35 mmol/L) and by 33% after 4 weeks (to 0.91 ± 0.18 mmol/L) ( P P

Effects of a gluten-free diet on serum lipids and lipoprotein (a) levels in a group of patients with celiac disease.

SummaryThe influence of nutrient absorption, caloric content, and diet on lipoprotein (a) [Lp(a)J concentration is uncertain. To our knowledge, there are no reports on Lp(a) behavior in malabsorption. Serum lipids and Lp(a) concentrations were evaluated in 17 celiac patients (5 male and 12 female patients; age range, 1–24 years) when the diagnosis was established and after a 3-month gluten-free diet. Mean total and low-density lipoprotein cholesterol did not show significant change, while mean high-density lipoprotein cholesterol rose and triglycerides decreased significantly after the diet. The Lp(a) concentration remained unchanged in all patients (median values, 35 mg/L before and 40 mg/L after the diet). Our results suggest that, in our patients, the lipoprotein profile was influenced by the gluten-free diet, while the Lp(a) concentration was not modified.

Impact of Testosterone Replacement on the Maturation of the Growth Hormone—IGF-I Axis

The regulated mode of growth hormone (GH) secretion is sexually dimorphic in both animals (1) and humans (2–6). During human pubertal development, there is preferential augmentation of the amplitude of spontaneous GH pulses, with a subsequent return to or a fall below prepubertal values in early adulthood (2). Some clinical data indicate a sex difference in the timing of these physiological changes in activity of the somatotropic axis (3). Moreover, a large body of evidence has been accumulated showing significant sex differences in GH responses to various pharmacological stimuli in young adults (4). However, the majority of data on sex hormone-mediated regulation of spontaneous and stimulated GH secretion in the human has been derived from cross-sectional population studies including healthy subjects of normal stature representing one or more stages of pubertal development (2,5,6). In relation to the specific actions of testosterone on GH secretion, these previous experiments have suggested an augmentation of the calculated maximal rate of GH release attained per secretory episode, resulting in a greater mass of GH released per secretory burst (6). A positive correlation between the magnitude of plasma GH responses to some provocative stimuli and androgen concentrations in human subjects (6) has also been suggested by cross- sectional studies.

Severe microvascular disease in type II diabetes of early onset. A family study

SummaryBoth early onset and late onset type II diabetes were present in one family of nine siblings. The three early onset type II diabetic siblings showed severe microvascular complications: proliferative retinopathy, diabetic nephropathy, and peripheral neuropathy. Early onset type II diabetes was not associated with any particular HLA haplotype. Early onset type II diabetes could be considered a clinical and genetic disease entity different from MODY type diabetes.