neurobehavioral and neurocognitive Features
While viewed as non- classical manifestations of PHPT, these features such as easy fatigability, anxiety, poor concentration, cognitive decline, and reduced quality of life are among the most vexing. The clinician is often faced with these complaints in the context of many other chronic diseases. Thus, they lack specificity. Another problem is that they are very hard to quantitate with reproducible metrics that can tract changes after parathyroid surgery. The confounding variables among the reports that have attempted to link neurocognitive and neuropsychiatric features to PHPT include study design (observational vs. prospective), selection bias, small numbers of study subjects, heterogeneity of bassline manifestations, short testing intervals after parathyroid surgery, and problems with control groups selected for comparison.
Even with newer testing instruments to test quality of life and cognitive function, some studies have shown improvements while others have not. As a result of these inconclusive studies, it is difficult to make any recommendations regarding surgical intervention in these patients who otherwise do not meet the generally agreed upon guidelines for parathyroid surgery in this disease.
cardiovascular Manifestations
The cardiovascular manifestations of primary hyperparathyroidism used to be heralded by hypertension, but now, with many patients demonstrating only modest hypercalcaemia, hypertension is no longer regarded as a feature of the disease. The problem with a common disease such as hypertension is that to demonstrate a clear association, one would have to show unequivocally that after para thyroid surgery, the condition is ameliorated. The older published literature provided some support for this link, but it is much more likely now not to see a difference in blood pressure after parathyroid surgery.
Coronary artery disease was linked to PHPT when the disease was associated with higher calcium levels than are seen today. Most current studies do not show that patients with PHPT have a greater incidence of coronary calcification beyond those acknowledged risk factors for coronary calcification. In a similar manner, calcifications of the myocardium and cardiac valves are seen only when patients have marked hypercalcaemia.
Left ventricular mass index (LVMI) is another focus for studies that have attempted to link PHPT to the cardiovascular system. While some studies have associated the PTH level itself, and not the blood pressure, with LVMI, other studies have not been confirmatory when other cardiovascular risk factors are taken into account. Again, conflicting data emerge with regard to regression of LVMI after parathyroidectomy.
Calcium concentration and carotid plaque thickness may be related but as shown by Walker et al. after adjustment for cardiovascular risk factors, parathyroidectomy was not associated with improvement.
Vascular dysfunction has been observed both in severe PHPT and in patients whose serum calcium is only mildly elevated.
Thus, despite a plethora of data regarding PHPT and cardiovascular manifestations, the results are inconclusive with regard to all the indices that have been measured. This is not to say, however, that the symptomatic form of PHPT is not be associated with cardiovascular manifestations. In fact, it is probably only in the symptomatic cohorts of patients with PHPT that one is likely to observe these manifestations.
Malignancy
Reports associating cancers with PHPT are subject to qualification due to the likelihood of selection bias. Hypercalcaemia usually triggers a search for malignancy since in its differential diagnosis, cancer is high on the list. Another aspect of selection bias relates to the common discovery of thyroid malignancy in patients who undergo parathyroidectomy. Thyroid cancer probably would not have been discovered were it not for the parathyroid surgery. In contrast, Wermers et al. have reported death due to cancer is reduced in PHPT with a hazard ratio of 0.58.
Mortality
Mortality rates in PHPT appear to follow the dictum that the more severe the disease is the more likely mortality will be increased. In cohorts of mild hypercalcaemia, mortality does not seem to be increased while more symptomatic cohorts show an increase in mortality. Supporting this expectation, mortality rates do correlate with the level of the serum calcium as well as parathyroid gland weight [150]. The experience from the Mayo Clinic also attributed higher mortality only in the quartile that had the highest serum calcium level. However, an epidemiological study has reported increased mortality and morbidity in ‘mild hyperparathyroidism’. Nevertheless, with the common phenotype of mild hypercalcaemia seen in many parts of the world, it would appear that mortality rates are not increased in PHPT.
the Variable clinical Expressions of Primary Hyperparathyroidism
The symptomatic disorder. Primary hyperparathyroidism was ushered into clinical recognition as a symptomatic disorder in the period from 1930 and 1970, It was truly a disease of bones and stones with serum calcium levels that were invariably over 12 mg/ dl, and often much higher.
The asymptomatic disorder. In the 1970s, when biochemical screening became widespread in many countries, the form of PHPT that we call ‘asymptomatic’ began to dominate the clinical land scape. Identifying these patients with mild hypercalcaemia and no overt bone or stone disease as asymptomatic seemed reasonable. As described in this chapter, it is now evident that among patients who are discovered incidentally, more diligent studies using modern technologies that can detect skeletal and renal involvement, upon further inspection, will reveal that the disease often does involved those classic organ systems. With signs of skeletal and/ or renal involvement, it might be time to reclassify these patients. Perhaps they are asymptomatic but they do demonstrate target organ involvement. Taking this concept one step further, if we reach a point where we can be confident of tools to measure neurocognitive and neuropsychiatric features, some of these patients might be classified as symptomatic.
The normocalcaemic disorder. After mild hypercalcaemia become the most common biochemical feature of PHPT, another four decades passed before the third variant of this disease, namely normocalcaemic PHPT became widely recognized. These patients are not being discovered incidentally, as patients with mild hypercalcaemia are identified, but rather in the context of being evaluated for low bone density or frank osteoporosis. Paradoxically, these patients demonstrate at the time of presentation more signs of the disease than those with mild hypercalcaemia. Routine measurement of PTH in these settings explains how normocalcaemic PHPT became recognized. We now know that normocalcaemic PHPT can be discovered without low BMD if population screening is undertaken [156]. Thus, as is the case for the hypercalcaemic variant, normocalcaemic PHPT can be asymptomatic or symptomatic.
An international View of clinical Variability in Primary Hyperparathyroidism
The historical perspective of PHPT implies a chronology of evolution. Symptomatic PHPT evolved to an asymptomatic disease which in turn evolved into a normocalcaemic disorder. This 90- year historical perspective can be misleading because it implies that the disease has actually changed. Given that all three forms of PHPT exist concurrently in the world today, another perspective argues that these three forms of PHPT have always coexisted. What sets the clinical stage for one or another variant may well be dependent upon country- specific factors. For example, in countries where bio chemical screening is not part of the healthcare system, such as India, patients are unlikely to be discovered incidentally. In these countries, symptomatic PHPT is more likely and, as was the case throughout the world prior to the 1970s, the disease in those countries is considered to be uncommon. In our more modern approach to country- wide health and biochemical screening, asymptomatic PHPT has become the more common variant. It is not considered to be a rare disorder. Parenthetically, as noted already, the use of the term asymptomatic probably needs some adjustment, even if only semantically, because with greater imaging tools ap plied to this population, it is apparent that such patients can often be shown to have involvement of the skeleton and/ or kidneys. Finally, in countries where PTH is routinely measured in the context of low BMD, normocalcaemic PHPT becomes a recognized clinical entity. The point to be made here is that PHPT has probably always existed in all three forms. The proportion of the hyperparathyroid population that will show them will depend upon these factors. Another consideration is the extent to which the population is vitamin D deficient. As noted already, vitamin D deficiency is associated with more signs of active disease. In a country that is markedly vitamin D deficient, on average, and does not employ widespread population screening, PHPT is likely to be viewed as an uncommon, symptomatic disorder. In a country that is not markedly vitamin D deficient, on average, and employs widespread population screening, PHPT is likely to be viewed as a common, asymptomatic disorder.
