Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series.

BACKGROUND: Reports since 2006 have identified proton-pump inhibitor (PPI) therapy as a cause of hypomagnesaemia, in a total of 13 cases. AIMS: To summarize the clinical course of 10 patients (one male, nine female) identified with severe hypomagnesaemia, all of whom were on PPI therapy. A case report illustrates the experience of a severely affected patient. METHODS: Clinical and biochemical review. Severe hypomagnesaemia was defined as 0.54 mmol/l or less, >4 SD below the mean. RESULTS: Patients were 68.8 +/- 8.6 years old when they presented with severe hypomagnesaemia, having been on PPI therapy for a mean of 8.3 +/- 3.5 years. Eight patients were on diuretics at initial presentation. There was significant morbidity as eight patients remained on PPI therapy after presentation for a mean of 2.75 +/- 1.54 years. There were 18 emergency hospital admissions with severe hypomagnesaemia. Oral and parenteral magnesium supplements were relatively ineffective at correcting the problem, but stopping PPI therapy lead to prompt resolution of the hypomagnesaemia (within 2 weeks in five carefully monitored patients), with symptomatic benefit. Hypomagnesaemia recurred if PPI therapy was re-introduced because of troublesome dyspepsia. However, pantoprazole, the least potent PPI, largely relieved dyspepsia and hypomagnesaemia did not inevitably develop when combined with oral magnesium supplements. CONCLUSION: These cases confirm that long-term PPI therapy can cause severe, symptomatic hypomagnesaemia, which resolves when PPI therapy is withdrawn. The serum magnesium should be checked annually in patients on long-term PPI therapy, or if they feel unwell.

Rheumatoid disease presenting as a nephrotic syndrome.

A 62 year old man with no relevant previous history presented with a nephrotic syndrome. Renal biopsy showed a membranous glomerulopathy and coincident investigation showed high serum titres of rheumatoid factors. It was not until some months later that he developed articular and extra-articular manifestations of rheumatoid arthritis.

Respiratory sinus arrhythmia in diabetic neuropathy.

Heart rate variation was measured at different rates of regular deep breathing (2.5 to 13 breaths/min) in 11 normal subjects and 13 diabetic patients with neuropathy, defined clinically by the absence of both ankle jerks or the presence of autonomic symptoms. Subjects were divided into those above and below 30 years old. Normal subjects showed twofold changes in heart rate variation with maximum variation at mean breathing rates of 6.3 and 5.5 breaths/min. Heart rate variation was significantly smaller than normal in the diabetic patients with neuropathy, at all of the frequencies tested in the younger group and 7 of the 13 test frequencies in the older group; the maximum variation occurred at slower mean breathing rates of 4.5 breaths/min (p less than 0.005) and 4.1 breaths/min (p less than 0.01) respectively. Seven diabetic patients without neuropathy, with intact leg reflexes and less than 30 years old, had normal heart rate variation but the maximum responses occurred at a mean breathing rate of 5.4 breaths/min, significantly slower than normal (p less than 0.02). Measuring the breathing rate at which heart rate variation is maximal may be a sensitive way of detecting autonomic (vagal) neuropathy.

Diabetic autonomic neuropathy. The diagnostic value of heart rate monitoring.

The use of heart rate monitoring in the diagnosis of diabetic autonomic neuropathy, and its value in observing the natural history of this disorder, has been assessed. Two tests were used: measurement of heart rate variation during deep breathing and of heart rate change on standing up. Two hundred and eighty seven diabetics aged between 20 and 49 years were studied, and 21 of them were observed repeatedly over 3 to 5 years. Heart rate variation (HRV) on deep breathing proved to be the more sensitive diagnostic index of autonomic neuropathy and was abnormal or borderline in 62 of 64 patients with established autonomic symptoms. Autonomic abnormalities were also detected in some diabetics without autonomic symptoms especially in those with peripheral neuropathy, 30% of whom had abnormal HRV on deep breathing. Abnormal tests appeared to represent permanent autonomic damage and may be present for years without the development of autonomic symptoms, occasionally (7%) preceding any other manifestation of diabetic neuropathy. Serial observations of HRV on deep breathing over 3 to 5 years showed little change, although overall there was a small deterioration of autonomic function, with a decrease of HRV score of 1.0 per year. The tests used are simple, and provide quantitative bedside measurements of autonomic function. When heart rate variation is normal, autonomic neuropathy is virtually excluded.

Pathology of autonomic neuropathy in diabetes mellitus.

Pathologic changes in the autonomic nervous system were studied postmortem in five cases of insulin-dependent diabetes of early onset. All had had clinical evidence of peripheral sensorimotor neuropathy and developed disturbances of autonomic function that included postural hypotension, diarrhoea, bladder dysfunction, impotence (in the men), and signs of cardiac denervation. In coeliac and other sympathetic ganglia there were many distended ('giant') or vacuolated neurons as well as enlarged club-shaped neural processes. The vagus nerve and sympathetic trunks showed severe loss of myelinated fibres. Smooth muscle in many viscera showed a hitherto undescribed focal hyaline degeneration. There were inflammatory changes in the autonomic ganglia in all cases and in or around bundles of unmyelinated nerve fibres in many. These findings suggest that there may be several different pathogenetic mechanisms involved in the development of autonomic neuropathy in diabetes.

Cardiac denervation in diabetic neuropathy.

Measurement of heart rate variation during deep breathing has been used as a diagnostic test of autonomic function. Normal subjects have considerable heart rate variation that is accentuated during deep breathing; this variation is diminished or sometimes absent in diabetics with autonomic neuropathy. Recording heart rate variation during deep breathing is a good method for establishing the presence of autonomic neuropathy: All normal subjects have a score greater than 9, and autonomic neuropathy is probably absent if the score is greater than 12. The optimal breathing rate for this test is six breaths per minute in nondiabetics but is usually less in diabetics with autonomic neuropathy. The use of six breaths per minute as a standard, however, enhances the ability of the test to discriminate normal from neuropathic patients. Imparied heart rate variation can be the earliest sign of diabetic neuropathy and may precede the appearance of autonomic symptoms by several years. Severe autonomic neuropathy may be responsible for spontaneous respiratory arrest and unexplained sudden deaths, which are not rare among these patients.

Assessment of diabetic autonomic neuropathy using heart rate monitoring.

Heart rate (HR) monitoring has been used for the diagnosis of diabetic autonomic neuropathy (AN). Two tests were used: measurement of heart rate variation (HRV) during deep breathing and measurement of HR changes on standing up. Three-hundred and one diabetics between 20 and 49 years old were studied, and 21 of them were observed repeatedly over 3-5 years. HRV on deep breathing was the most sensitive diagnostic test of AN, and was abnormal in 84% of 64 patients with established autonomic symptoms. Autonomic abnormalities were also detected in diabetics without autonomic symptoms, especially those with peripheral neuropathy. Abnormal tests represent permanent autonomic damage and may be present for several years before the development of autonomic symptoms. Occasionally they represent the earliest manifestation of diabetic neuropathy.

Progression of diabetic nephropathy.

Although deterioration of renal function in diabetic nephropathy varies considerably from one diabetic to another, its rate is constant in individuals. For each patient there is a linear relation between period (months) which elapses from the time serum creatinine becomes greater than 200 mumol/l and the inverse the inverse of the serum-creatinine. The observation is of practical importance in predicting the time at which end-stage renal failure will develop, so that treatment can be planned in advance.

Cardiovascular effects of insulin: plasma volume changes in diabetics.

The mechanism by which insulin can alter the heart-rate and blood pressure of diabetics has been studied. Insulin decreased the plasma volume of 16 diabetics without complications by an average of 190 ml, a 6% change. Nine diabetics with severe autonomic neuropathy had no significant change in plasma volume after insulin. The basal plasma volume of autonomic neuropathy patients was smaller than that of the uncomplicated diabetics, perhaps accounting for the disparity observed between these two groups of diabetics. The decrease of plasma volume could thus account for the heart rate increase of uncomplicated diabetics, but not for the induction of hypotension in those with autonomic neuropathy.

Intravenous insulin infusion in diabetic emergencies.

Continuous intravenous insulin and dextrose infusions were used in managing various diabetic emergencies. Standard and constant rates of insulin and dextrose infusion resulted in satisfactory control of blood glucose concentrations during labour, after major surgery, and in patients recovering from ketoacidosis (average insulin infusion rates 1, 2, and 3 U/h respectively). Higher infusion rates were used to correct or prevent ketoacidosis in pregnant diabetic women who had received steroids and sympathomimetic agents. The infusion method is simple, reliable, and flexible, and may help to simplify management of diverse types of diabetic emergencies.