Impaired Quality of Life and Cognitive Function in Patients With Hypoparathyroidism Might be Explained by Disturbed Capillary Flow Patterns in the Brain

Hypoparathyroidism (HypoPT) is a disease with inadequate production of parathyroid hormone (PTH) from the parathyroid glands leading to hypocalcemia. The most common form is postsurgical HypoPT due to neck surgery resulting in removed or damaged parathyroid glands. Postsurgical HypoPT has a prevalence of 22/100,000 inhabitants in Denmark. Nonsurgical HypoPT is most often caused by mutations in different genes or on an autoimmune basis, the prevalence of nonsurgical HypoPT is 2.3/100,000 inhabitants in Denmark. If the gene mutation is within the GNAS gene or upstream of the GNAS complex locus it causes PseudoHypoPT (PHP), which is characterized by target organ resistance to PTH, also resulting in hypocalcaemia and hyperphosphatemia as in post- and nonsurgical HypoPT, but in this case with high or normal levels of plasma PTH. PHP is a very rare disease with a prevalence of 1/100,000 inhabitants in Denmark.

Others and the investigators have previously shown that HypoPT and/or hypocalcemia may affect quality of life (QoL). In most cases, severe symptoms and findings diminished or disappeared when plasma calcium levels are restored to normal, but as some of the above mentioned studies have shown, the reduced QoL is still present despite normal calcium levels. Symptoms are describes as minor cognitive impairment (MCI), with confusion, forgetfulness, and lack of focus and mental clarity. Another important finding in some of the patients with HypoPT is calcifications of the basal ganglia as described in several case reports, the knowledge of the origin and importance of these is so far limited. Patients with PHP have previously been described to have a higher risk of calcifications of the lens and subcutaneous calcifications, and therefore might also be at higher risk of calcifications in the brain.

The oxygen availability in brain tissue is traditionally thought to depend on regional cerebral blood flow (CBF). Accordingly, brain oxygenation is only expected to impair brain function in cases where CBF is critically reduced, cerebral ischemia. This paradigm was recently shown to be in error: While CBF determines the oxygen supply, the microscopic distribution of blood flows across the capillary bed determines the extent to which this oxygen can be extracted by the tissue. In fact, capillary flow patterns can become so disturbed that the metabolic needs of brain function and survival can no longer be met - although CBF remains inconspicuous. Capillary dysfunction denotes this overlooked source of hypoxia: A state in which capillary flow patterns cannot homogenize, giving rise to tissue hypoxia, oxidative stress, local inflammation, and - if severe - long-term neurodegeneration. The investigators hypothesize that the symptoms of HypoPT patients represent various degrees of capillary dysfunction, which interfere with their brain function.

The purpose of the study is to investigate whether HypoPT patients are affected by capillary dysfunction, a condition in which capillary flow disturbances interfere with brain oxygenation.

The hypothesis derives from findings that cerebral calcifications similar to those found in HypoPT are observed in familial idiopathic basal ganglia calcification (IBGC), which is a disease of cerebral pericytes. Pericytes are localized in the basement membrane of capillaries, where they maintain blood brain barrier (BBB) function and - in close interaction with endothelial cells - basement membrane and capillary wall integrity. They are contractile and take part in blood flow regulation. They control the trafficking of immune cells across the vessel wall and possess stem/progenitor cell functions. As such, they play a key role in tissue repair, scarring, and fibrosis, and along with endothelial cells, they seemingly have the potential to become bone-forming cells.