Hormonal dysfunction in adult patients affected with inherited metabolic disorders

Primary or secondary hypogonadism is commonly associated with IMDs. Haemochromatosis (HFE) is the most common cause affecting the pancreas, pituitary gland and gonads with an accumulation of iron. As a result, patients present with hypo-or hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism has been found in 5.2% (n=38) female patients and 6.4% (n=141) male subjects, 89% of whom also have had cirrhosis and 33% diabetes (4). Given that the endocrine abnormality may be the first indicator of an IMD, HFE should always be suspected in male subjects with isolated hypogonadotropic hypogonadism. Pituitary iron overload, as well as the HFE and transferrin genotype, may explain the hypothalamic-pituitary gonadal involvement (5). If diagnosed early, clinical manifestations can be prevented or improved through regular venesection (phlebotomy). The benefits of treatment with androgens has to be carefully balanced in view of their potentially carcinogenic role and increased risk of hepatocarcinoma when associated with cirrhosis (6).

The underlying mechanisms by which thyroid abnormalities occur are complex and incompletely understood. It is suspected that a lack of adenosine triphosphate production and/or increased oxidative stress in endocrine cells with impaired mitochondria may lead to failure of hormonal synthesis and/or secretion (35). A few associations with specific nuclear encoded genetic defects have been noted, particularly in TANGO2 and PTRH2 mutations, but insights about the presence of a causal mechanism between mitochondrial disease and thyroid dysfunction are lacking. The overall prevalence of hypothyroidism, the most common thyroid abnormality, has been estimated as 6.3% (51) and increases with age. Goitre has also been reported. Energy defects could impair thyroperoxidase, lowering the production of thyroid hormones, which themselves are involved in mitochondrial metabolism, therefore worsening the mitochondrial dysfunction (1).

Several IMDs are associated with dysthyroidism in adulthood and mainly involve energy metabolism defects and the degradation or synthesis of complex molecules. Given that GSD Ib is associated with neutropenia that increases the risk of autoimmune infections, there is an increased prevalence of autoimmune hypothyroidism with raised thyroid-stimulating hormone (TSH), thyroglobulin levels and antithyroperoxidase antibodies (52). Another possible pathomechanism of abnormal thyroid function tests in patients with GSD is their chronic liver disease. There has been a negative correlation between free T3 levels and direct bilirubin, suggesting an association between the disease severity and the thyroid function test (53). Euthyroid sick syndrome or subclinical hypothyroidism was documented in GSD patients with chronic liver diseases (53).

This rare non-lysosomal lipid storage disorder, caused by defects in two triglyceride-associated proteins, results in impaired degradation of triglycerides and causes their accumulation in cells with two different phenotypes (54). Apart from myopathy, cardiomyopathy, ichthyosis, hepatomegaly or central nervous system involvement, thyroid nodular dystrophy related to intracellular accumulation of triglycerides have been reported (55). Abnormal lipid metabolism may lead to other endocrine abnormalities such as low leptin and adiponectin levels, a moderate increase in insulin levels at fasting state and even greater increase after oral glucose tolerance test (56).

Thyroid function tests are frequently abnormal in children with CDG (17, 57), in whom congenital hypothyroidism has been suspected. In adults with CDG, clinical hypothyroidism is rare (1). As part of the follow-up protocol, thyroid hormones including TSH, free T3 and free T4 should be measured. Low thyroxine-binding globulin (TBG) and transient elevations in TSH were previously documented (17, 57).

Subclinical dysthyroidism is frequent and resolves with enzyme replacement therapy (ERT). Subclinical, non-autoimmune hypothyroidism was observed in 30% of cases in an untreated series (32). In some cases, however, undiagnosed hyperthyroidism may aggravate adverse reactions to ERT (32). It highlights the importance of requesting hormonal profile in all patients before ERT is considered (personal observations).

Progressive cystine accumulation and crystal formation in thyroid follicular cells causes fibrosis and atrophy leading to primary hypothyroidism in 50–75% of patients with cystinosis (1, 28), manifesting in the majority of patients from the second decade of life (29). Impaired thyroglobulin synthesis and iodo-thyroglobulin processing might be responsible for subclinical hypothyroidism with TSH elevation and normal T3 and T4 plasma concentrations (29). Importantly, HSCT has been shown to correct thyroid disease in mice (58), which was not documented in human beings.

The mechanisms of adrenal dysfunction vary. This common finding in X-linked ALD is caused by defective catabolism resulting in VLCFA accumulation, which interferes with steroid hormone synthesis. In adulthood, adrenal insufficiency, which generally appears after the age of 3–4 years, is present in 70% of patients. It can be the first and only manifestation of the disease for decades. Its association with neuropathy suggests the diagnosis. At the age of 20, it is usually associated with hypergonadotropic hypogonadism (1).

Importantly, the peptide hormones β-lipotropin (β-LPH) and β-endorphin were found to be localised to peroxisomes in various human tissues (59). This suggests a functional link between peptide hormone metabolism and peroxisomes. In addition, it has been postulated that peroxisomes are involved in steroidogenesis because patients affected with peroxisomal disorders have endocrine manifestations that affect steroid hormones (59).

Adrenal dysfunction is a common complication of several LSDs and results from storage material accumulation in adrenal glands, e.g. Fabry disease (60), cystinosis (30) or Niemann Pick B; a non-neurologic, visceral form with hepatosplenomegaly, pulmonary disease and survival into adolescence and/or adulthood (45).

Mitochondrial disease-related adrenal insufficiency is rare in childhood; however, this may be the first symptom (60) and is associated with poor prognosis (1, 61). In adulthood, subclinical adrenocortical insufficiency is sometimes found in multisystemic forms as shown in cases affected with POLG mutation (62). Various types of aldosterone secretion disturbances, mainly secondary hyperaldosteronism possibly associated with tubulopathies, have also been reported (63).

Lesch-Nyhan syndrome, a rare X-linked recessive disorder of purine synthesis, is characterised by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT). The adrenal medulla may be directly affected by the absence of HPRT enzyme. Polyendocrinopathy is typical of this condition and has been previously documented (64). The deficiency of the normally high activities of HPRT in the testes appears to inhibit their ability to respond to gonadotrophin (64). Boys often present with growth delay, testicular atrophy and a partial failure of the 11 beta-hydroxylation of steroids (64). Persistently low cortisol with satisfactory short synacthen test has been previously reported although mechanisms were unclear (personal observation).

Adrenal insufficiency is a common endocrine complication of SLO syndrome (65, 66). It is recommended that all patients affected with this condition have morning serum cortisol and pituitary gland hormones and electrolytes checked prior to any surgical intervention and during the acute illness to ensure early intervention to correct these biochemical consequences, to reduce mortality and to improve long-term outcome (66).

Hereditary HFE caused by a mutation in HFE 1 gene is one of the most frequent metabolic diseases and the penetrance is variable and modulated by environmental factors such as body weight and alcohol.

Non-transferrin-bound iron plays an important role in cellular iron damage through an increase in oxidative stress. First, liver iron overload promotes the occurrence of insulin-resistant diabetes (70). The pancreas ß cells may then be progressively destroyed, leading to C-peptide negative diabetes and requiring insulin therapy besides iron depletion.

Aceruloplasminemia is characterised by the accumulation of iron in the liver, islets of Langerhans and the brain, related to decreased cellular iron egress, in contrast with most other types of iron overload (71). The treatment with fresh frozen plasma infusion and iron chelation is efficient in reducing iron overload and preventing both neurological involvement and diabetes in this condition (personal observation).

Disorders of energy metabolism such as GSDs comprise the other mechanisms of diabetes development in IMDs. GSDs are associated with the highest number of endocrine anomalies. Glycogen deposits and secondary glycosylation disturbances in GSDs (in which only the pancreas and ovaries are affected) are the most probable mechanisms involved in these disorders (1).

GSD is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver and other cell types. Type I GSD is initially associated with severe fasting hypoglycaemia.

Postprandial hyperglycaemia can occur in adulthood (1) and is likely to be associated with recurrent pancreatitis and hypertriglyceridaemia, which lead to insulin secretion impairment or an adaptive mechanism of the glucose receptor, GLUT2, for reducing the secretion of insulin. Diabetes is also promoted by insulin resistance related to liver and/or muscle dysfunction (72, 73).

Apart from GSD type I and III, diabetes mellitus has become a common feature of GSD V (McArdle syndrome) with 30% of adult patients affected with this condition (personal observation).

Endocrine and exocrine pancreatic insufficiency is a long-term complication of cystinosis, an organelle disorder, usually after renal allograft transplantation (29). Up to 50% of infantile cystinosis patients by the second decade of life develop slow progressive loss of insulin secretion and C-peptide production leading to glucose intolerance and diabetes mellitus (1, 29, 74; 87). These complications are only partially prevented or improved with cysteamine treatment (1).

Mitochondrial diabetes accounts for 0.06–2.8% of cases of type 2 diabetes. The diagnosis should be considered in young, lean patients with non-autoimmune diabetes and neurosensory or muscular involvement (1). A higher level of heteroplasmy has been found in mitochondrial diabetes in the endocrine pancreatic ß cells than in the exocrine cells and blood leucocytes (75).

There are different forms of mitochondrial diabetes (76, 88) and may be associated with multiple endocrine dysfunctions. In mitochondrial diseases impaired pancreatic ß cell function is a result of ATP deficiency (77). The production of ATP through the glycolysis pathway, too low to ensure normal cell function, leads to cell death, as confirmed histologically by a reduction in the number of ß cells (1, 78). It also prevents closure of the potassium channels, inducing a defect in insulin secretion (79). Insulin sensitivity in skeletal muscle is also decreased (79). As a result, insulin requirement may increase with occasional ketoacidosis. Proteinuria and renal insufficiency occur more frequently than usual in diabetes (1).

Endocrine abnormalities including hyperprolactinemia, growth hormone release with hyperglycaemia, insulin resistance, and hyperinsulinemic hypoglycaemia have been described in CDG (16, 17). A recent review by Moravej et al. confirmed that hypoglycaemia is associated with hyperinsulinism in 43% of phosphomannomutase 2 deficiency (PMM2-CDG) patients (80). Most patients with phosphomannose isomerase deficiency (MPI-CDG) develop hypoglycaemia, but due to the often-severe gastrointestinal symptoms, moderate episodes of hypoglycaemia may be compensated for or masked by frequent enteral and parenteral nutrition (80, 81). Most patients with phosphoglucomutase 1 deficiency (PGM1-CDG) develop hypoglycaemia, which seems to be because of multifactorial: hyperinsulinism, inappropriate counter-regulatory hormonal response (low cortisol), impaired glucose release from glycogen during fasting and malnutrition (82). Most cases are managed conservatively, but in some others, diazoxide was used (80).

Diabetes has occasionally been described in patients with Wilson’s disease. Excessive fat deposition in liver and nuclear glycogen deposition contributing to hepatic insulin resistance has been postulated in these individuals (47).

This rare disorder resulting from a defect in ALMS1 protein localised to the centrosomes and basal bodies of ciliated cells is characterised by short stature, renal failure, dilated myocardiomyopathy, blindness and deafness (1, 83). About 92% of patient with this syndrome develop insulin resistance before the age of 16, obesity and primary hypogonadism (in males) and PCOS and hirsutism in females (1).

Some mitochondrial disorders such as mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) due to point mutations in mitochondrial tRNA; long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or combined mitochondrial trifunctional protein (MTP) deficiency due to mutations in MTP (84); medium-chain acyl-CoA dehydrogenase deficiency (MCADD) due to mutations in the ACADM gene (85, 86). The mechanism by which these mitochondrial defects affect parathyroid gland development or function is unknown (86).

No obvious endocrine consequences have been described so far in aminoacidopathies or urea cycle disorders (1).

IMDs are commonly associated with endocrinopathies, which remain undiagnosed in many cases. Hormonal profiling should be part of the routine blood test panel to diagnose asymptomatic endocrine disorders with delayed manifestations. It is worth considering screening for common hormonal dysfunction when patients are symptomatic. In some adult-onset cases presenting with multiple endocrinopathies, the diagnosis of an IMD should be suspected.

Given that new therapies are in development, e.g. gene therapies, stem cell therapies, pharmacological chaperone and substrate reduction therapies, clinicians should be aware of their potential effect on the endocrine system.