Gout (Hyperuricemia): Causes

Pathogenesis (development of disease)

Uric acid represents the end product of purine breakdown in the liver and intestines. Approximately 700 mg of uric acid is formed per day. Purines are ingested with food. Foods that are rich in purines are those that have a high proportion of cells and consequently of cell nucleus material. These include meat and sausage, offal, fish, the skin of poultry and legumes. Fruits and vegetables are low in purine, and protein sources such as milk, cheese and eggs are purine-free.After ingestion of food containing purine, uric acid turnover increases 100-400-fold. 10% of uric acid is excreted and 90% is used for de novo purine nucleotide synthesis. 20-30 % of uric acid is excreted via the intestines and 70-80 % via the kidneys (renal uric acid excretion). Based on the cause, the following forms of hyperuricemia are distinguished:

  • Primary familial hyperuricemia (idiopathic or familial hyperuricemia):
    • Increased synthesis of uric acids in the presence of a defined enzyme defect (eg, a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase; HGPRTase for short) <1%.
    • Disorder of renal uric acid excretion – 99% of cases; appears to be inherited polygenically and is quite common (disease of affluence).
  • Secondary hyperuricemia – acquired as a result:
    • Decreased renal uric acid excretion: e.g., chronic renal failure.
    • Increased uric acid formation: e.g., hemoblastoses (collective term for malignant diseases of the hematopoietic system, e.g., leukemias) or excessive dietary purine intake (meat, beans).

Urate deposition occurs at a serum concentration of > 6.4 mg/dl (at 37 °C and a blood pH of 7.4), which is considered the solubility limit of uric acid. This occurs mainly in bradytrophic tissues (bone, cartilage, joint capsules, ligaments, vision). However, urate deposits also occur in bursae (bursitis), skin (gouty tophi) and muscles. Gout is more than a monoarticular joint disease (monarthritis/joint inflammation of the metatarsophalangeal joint). Precipitating uric acid crystals are phagocytosed (“eaten up”) and activate the multiprotein complex inflammasome in the cell. Caspases (group of cysteine proteases that cut target proteins at a peptide bond C-terminal of aspartate) are formed in response, and pro-interleukin-1 gives rise to interleukin-1-beta (IL-1β; counts as a proinflammatory cytokine). Thus, gout is an autoinflammatory disease (diseases with increased inflammatory activity). For details on “absorption and metabolism” of purines, see below Fundamentals of Nutritional Medicine/Purines.

Etiology (Causes)

Biographic Causes

  • Genetic burden
    • Genetic defects leading to an increase in uric acid production [frequency <1% of cases]:
      • Defects in, for example, hypoxanthine-guanine phosphoribosyl transferase (HGPRT).
      • Lesch-Nyhan syndrome (LNS; synonyms: hyperuricemia syndrome; hyperuricosis) – X-linked recessive inherited metabolic disorder of the rheumatic type (disorder in purine metabolism).
      • Phosphoribosyl pyrophosphate synthetase overactivity (PRPP) – X-linked inherited disorder of purine metabolism with increased synthesis of purine nucleotides and uric acid.
      • Glycogen storage diseases – group of disorders with both autosomal dominant and autosomal recessive inheritance in which glycogen stored in body tissues cannot be degraded or converted to glucose, or can be degraded only incompletely
    • Genetically determined limitation of the performance of the active secretion process in the renal tubule, enzyme defects leading to the disturbance of renal excretion of uric acid:
      • According to a genome-wide association study (GWAS), uric acid concentration is thought to be 25% to 60% determined by genetic factors
      • Gene variant of the fructose transporter gene SLC2A9 (about 5% of cases).
      • Gene variant in the ABCG2 transporter (SNP: Rs2231142, also known as Q141K):
        • Allele constellation: AA (causes hyperuricemia/gout; reduces uric acid transport by 53% compared with wild type (CC));
        • Allele constellation: AC (increases hyperuricemia risk by 1.74-fold).

        10% of all gout cases are due to the A allele

    • If one parent is affected, the own risk increases to 25%.
    • Genetic diseases
      • Bartter syndrome – very rare genetic metabolic disorder with autosomal dominant or autosomal recessive or X-linked recessive inheritance; defect of tubular transport proteins; hyperaldosteronism (disease states associated with increased secretion of aldosterone), hypokalemia (potassium deficiency), and hypotension (low blood pressure).
      • Polycystic kidney disease – kidney disease due to multiple cysts (fluid-filled cavities) in the kidneys.
        • Partly with autosomal dominant as well as autosomal recessive inheritance (see below Cystic Kidney Disease).
  • Hormonal factors – menopause (menopause).

Behavioral causes

  • Nutrition
    • Increased dietary purine intake, e.g., due to excessive meat consumption (especially offal)
    • Sugar substitutes sorbitol, xylitol and fructose in high doses – The consumption of soft drinks and the associated high intake of fructose leads to an increased risk of hyperuricemia or gout.
    • Fructose-containing beverages (fructose-sweetened soft drinks or even orange juice) lead to an increased risk of hyperuricemia in
      • Women who drank one fructose-sweetened beverage per day: 1.74-fold risk; ≥ 2 glasses: 2.39-fold risk
      • Men who drank one one fructose-containing drink per day: 1.45-fold risk; ≥ 2 glasses: 1.85-fold risk
    • High fat diet
    • Intake of: Potatoes, poultry, soft drinks and meat (beef, pork or lamb).
    • Fasting → Decreased renal excretion of uric acid.
    • Vitamin A-rich diet or, if necessary, vitamin A overdose through supplements.
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Consumption of stimulants
    • Alcohol (abuse), especially beer (also non-alcoholic beer); wine; liquor (woman: > 40 g/day; man: > 60 g/day).
  • Overweight (BMI ≥ 25; obesity).

Disease-related causes (secondary hyperuricemia).

  • Decreased renal excretion of uric acid
  • Increased uric acid formation due to increased purine release by increased cell turnover or cell decay.
    • Hemoblastoses (collective term for malignant diseases of the hematopoietic system, e.g. leukemias, polycythaemia vera).
    • Hemolytic diseases – blood diseases associated with hemolysis (dissolution of red blood cells).
    • Lymphoproliferative diseases
    • Malignancies (cancers)
    • Myeloproliferative neoplasms (MPN) (formerly: chronic myeloproliferative diseases (CMPE)): e.g. chronic myeloid leukemia) – malignant diseases of blood-forming organs.
    • Tumor lysis syndrome – life-threatening condition that can occur during the rapid decay of tumors (usually under chemotherapeutic treatment).
  • Increased uric acid formation due to increased purine synthesis.
    • Glycogenosis – glycogen storage disease – types I, III, V and VII.
  • Diseases associated with hyperuricemia:
    • Acromegaly – hormonal increase in size of the body end limbs or acra.
    • Apoplexy (stroke)
    • Arterial hypertension (high blood pressure)
    • Diabetes insipidus – disorder in hydrogen metabolism leading to extremely high urine excretion (polyuria; 5-25 l/day) due to impaired concentration capacity of the kidneys.
    • Impaired glucose tolerance to diabetes mellitus.
    • Glucose-6-phosphatase deficiency
    • Hypercalcemia (excess calcium)
    • Hypercholesterolemia – Fredrickson type II
    • Hyperparathyroidism (parathyroid hyperfunction).
    • Hypertriglyceridemia – increased triglycerides (blood fats).
    • Metabolic syndrome – clinical name for the symptom combination obesity (overweight), hypertension (high blood pressure), elevated fasting glucose (fasting blood sugar) and fasting insulin serum levels (insulin resistance) and dyslipidemia (elevated VLDL triglycerides, lowered HDL cholesterol). Furthermore, a coagulation disorder (increased tendency to clotting), with an increased risk of thromboembolism can often be detected.
    • Myocardial infarction (heart attack)
    • Obstructive sleep apnea syndrome (OAS; characterized by obstruction (narrowing) or complete closure of the upper airway during sleep; most common form of sleep apnea (cessation of breathing during sleep)) – 5.8 years after OSA diagnosis, 4.9 percent of subjects developed arthritis urica/gout-related joint inflammation (gout) compared with 2.6 percent in the non-OSA group; the association was most pronounced in subjects with normal body mass index (hazard ratio: 2.02 (1.13-3.62) 1-2 years after diagnosis).
    • Polyglobulia – increase in the number of red blood cells (RBCs) above normal.
    • Psoriasis (psoriasis)
    • Respiratory acidosis (respiratory hyperacidity).
    • Sarcoidosis (synonyms: Boeck’s disease; Schaumann-Besnier’s disease) – systemic disease of connective tissue with granuloma formation (skin, lungs and lymph nodes).
    • Trisomy 21 (Down syndrome) – genetic disease that occurs mostly sporadically; in which the entire 21st chromosome or parts of it are present in triplicate (trisomy) (occurrence mostly sporadic). In addition to physical features considered typical for this syndrome, the cognitive abilities of the affected person are usually impaired.

Medication

Radiotherapy

  • Radiatio (radiotherapy) – is often accompanied by increased necrolysis (tissue destruction).

Environmental pollution – intoxications (poisonings).

  • Beryllium
  • Lead – lead nephropathy (disease of the kidneys caused by lead poisoning).