endocrine and kidney diseases - uygur

Hyperuricemia Overview

• These are study notes for metabolic diseases, with a focus on hyperuricemia.
• Hyperuricemia is when uric acid (UA) production and excretion is unbalanced.
• Hyperuricemia levels are >7 mg/dL in males or >6 mg/dL in females.

Uric Acid and Urate

• Uric acid (UA) the end-product of purine metabolism in humans.
• Urates, ionized form of uric acid, is predominant in plasma, extracellular fluid, and synovial fluid, as monosodium urate at pH 7.4 (~98%).
• Urate production happens in tissues containing xanthine oxidase, mainly the liver and small intestine.
• Xanthine oxidase is critical for uric acid synthesis.
• Two-thirds to three-fourths of urate is excreted through urine by the kidneys.
• The intestines eliminate the remainder of urate.
• In the kidney, uric acid is filtered by the glomeruli and reabsorbed in the proximal tubule.
• Uric acid is secreted and partially reabsorbed in the distal proximal tubule, ascending loop of Henle, and collecting tubules.
• The normal uric acid pool: 1200mg for men and 600mg for women.
• Daily uric acid synthesis is about 400mg.
• Dietary sources contribute about 300mg.
• 75% of uric acid excreted in urine, the remainder in the GI tract and degraded to allantoin by bacterial enzymes.
• Guanine and Adenosine are purines in the body.

Purine Synthesis

• De novo purine synthesis uses the pentose phosphate pathway to produce Ribose-5-phosphate.
• Ribose-5-phosphate is converted by a synthase into phosphoribosyl pyrophosphate (PRPP).
• PRPP forms Guanine or Adenosine.
• Hypoxanthine can be obtained using the same pathway and is converted by xanthine oxidase into xanthine and then uric acid, which is excreted.
• The salvage pathway turns hypoxanthine directly into guanine and adenosine, recycling uric acid metabolites.
• The salvage pathway needs HGPRT (Hypoxanthine-Guanine phosphoribosyl transferase) to recover hypoxanthine and produce GMP, IMP, and AMP.

Pathogenesis of Hyperuricemia

• Hyperuricemia results from overproduction (10%) or underexcretion (90%) of uric acid.
• Overproduction is caused by enzyme defects, increased purine intake, alcohol intake, myeloproliferative disease, and psoriasis.
• Enzyme defects: overactive PRPP synthetase, HGPRTase defects, or other issues in purine synthesis (APRTase, ADA).
• Underexcretion is caused by renal defects, decreased glomerular filtration rate (GFR), diuretics, tubular toxins (alcohol, low-dose ASA, cyclosporine), lead, hypothyroidism, and organic acid accumulation.
• Accumulation of organic acid (DKA, starvation, lactic acidosis) competes with urate for tubular secretion.
• High fructose intake leads to rapid ATP depletion and increases uric acid production, contributing significantly to hyperuricemia.

Lesch-Nyhan Syndrome

• Lesch-Nyhan syndrome is a rare inheritable disorder causing hyperuricemia due to HGPRT deficiency.
• HGPRT deficiency impairs salvage synthesis, increasing uric acid synthesis.
• LNS affects about 1 in 380,000 live births.
• HGPRT defect increases hypoxanthine and guanine levels, increasing uric acid.
• HGPRT deficiency results in uric acid buildup in all body fluids, causing gout and kidney problems.
• Neurological signs: poor muscle control, intellectual disability, aggressiveness, self-mutilation, and head banging.
• Life expectancy: early to mid-20s.

Clinical Presentation and Treatment

• Hyperuricemia can be asymptomatic or cause gout.
• Gout is a metabolic disorder due to excess uric acid, causing monosodium urate crystal deposition in joints.
• Gout is the most common form of inflammatory arthritis in men >40 years old, with a prevalence near 4%.
• Incidence increases to near 10% with age therefore gout is an important cause of inflammatory arthritis in elderly patients.
• Uric acid levels increase significantly after 80 years.
• Elevated serum uric acid is the most correlated lab value with metabolic syndrome.
• Gout risk factors: advanced age (>65 y.o.), trauma to joints, hospitalization, high-meat-and-fish diet, and chronic renal insufficiency.
• Medications increasing gout risk: diuretics, nicotinic acid (niacin), low-dose aspirin, cyclosporine, ethambutol, pyrazinamide, and levodopa.
• Hyperuricemia is treated if cut-off is > 7 mg/dL for males and > 6 mg/dL for females.
• Drug treatment may be unnecessary for patients with a single gout episode where they are losing weight and reducing alcohol/fructose intake.
• Pharmacological treatment is indicated with frequent gout attacks, tophi, CKD (stage 2 or greater), or urolithiasis as target uricemia is <6mg/dl.
• Healthy lifestyle changes can prevent the need for drug treatment.
• Changes include weight loss, a healthy diet, exercise, smoking cessation, and hydration.
• Alcohol(especially beer), high-purines and fructose should be avoided in a correct diet.
• Patients should limit meat (poultry, crab, lobster, oysters, and shrimp) to 4-6 ounces daily.
• Limit vegetables high in purines such as asparagus, cauliflower, spinach, mushrooms, and green peas, to less than ½ cup each day.
• Consume beans and lentils up to 1 cup daily.
• Limit oats and oatmeal to 2/3 cup uncooked daily.
• Limit wheat germ and bran to ¼ cup per day to avoid high purine intake.
• Clinical trials have shown that these measures reduce serum uric acid by 10-15%.
• These lifestyle changes are insufficient in patients with maintained Hyperuricemia >7mg/dl.
• Avoid high-purine foods such as anchovies, sardines, scallops, mussels, tuna, codfish, herring, haddock, wild game meats, and organ meats.

Therapeutic Strategies

• The excretion of uric acid from the kidneys can be increased, or the de novo synthesis of uric acid can be decreased.
• Xanthine oxidase inhibitors can be used for excessive production of uric acid, such as allopurinol.
• For treating the inadequate excretion of uric acid, uricosuric agents exist.
• Restricting the dietary consumption of high-purine food can also be employed.

Xanthine Oxidase Inhibitors

• Allopurinol is a xanthine oxidase inhibitor, working as a competitive, nonselective enzyme inhibitor, decreasing uric acid synthesis.
• Febuxostat interacts similarly to allopurinol but is more potent.
• Febuxostat is selective for xanthine oxidase and binds to a specific region.
• Febuxostat and metabolites are excreted via the liver and kidneys, without dosage changes in kidney failure.

Uricosuric Agents

• Probenecid and Sulfinpyrazone increase uric acid excretion by blocking tubular reabsorption, enhancing urine uric acid excretion and decreasing serum uric acid levels.
• Probenecid is less effective in older patients and is contraindicated in a history of high uric acid, nephrolithiasis, and renal disease.

Gout

• Gout is the main clinical expression of hyperuricemia in the body.
• Inflammation of the first metatarsal joint is pathognomonic for gout arthritis.
• It is the most common form of inflammatory arthritis in men >40 years old, with a prevalence near 4%.
• Incidence increases to near 10% with age, therefore gout is an important cause of inflammatory arthritis in elderly patients.
• Uric acid levels increase significantly after 80 years.
• Elevated serum uric acid is the most correlated lab value with metabolic syndrome.
• Gout risk factors are advanced age (>65 y.o.), trauma to joints, hospitalization, high-meat-and-fish diet, and chronic renal insufficiency.
• Medications increasing gout risk: diuretics, nicotinic acid (niacin), low-dose aspirin, cyclosporine, ethambutol, pyrazinamide, and levodopa.

Gouty Arthritis

• The first episode of acute gout arthritis is usually preceded by hyperuricemia for years.
• The first metatarsal-phalangeal joint is pathognomonic, also occurring in other foot joints, ankles, or knees.
• Commonly monoarticular (80%) in the first cases, but can be polyarticular in recurrent cases.
• The first episode is frequently excruciating and builds up over several hours.
• The main characteristics in gouty arthritis include:
  • Sudden onset
  • Middle-aged males
  • Severe pain
  • Distal joints
  • Intense inflammation
  • Recurrent episodes
  • Influence by diet
  • Bony erosions on X-ray
  • Hyperuricemia
• High serum uric acid levels is a feature of gouty arthritis.

Acute Gout

• Main features includes:
  • Redness
  • Warmth
  • Pain
  • Tenderness
• The big toe joint is mostly affected.
• Bony erosions on the foot joints are sometimes visible on X-rays.
• Synovial fluid analysis shows monosodium urate crystals, which are pathognomonic for gouty arthritis.
• Synovial fluid analysis helps differentiate gouty arthritis from septic arthritis, where antibiotics are urgently needed.
• Differential diagnoses for gouty arthritis: Pseudogout, Reactive arthritis, Polyarticular arthritis, and Rheumatoid arthritis.
• Tophus, a clinical sign visible after several attacks, can be seen in joints and ears.

Drugs used to treat gout

• Acute arthritis drugs used to treat gout, lower inflammation and include:
  • Colchicine
  • Steroids
  • NSAIDs
• Urate-lowering drugs:
  • Allopurinol
  • Probenecid
  • Febuxostat
• Rest, analgesia, and time are also important for treatment.

Colchicine

• Colchicine is used to treat acute gouty arthritis, and in low doses, it can prevent recurrent gouty arthritis.
• Effective only in gouty arthritis.
• Colchicine is not:
  • An analgesic agent.
  • Affect renal excretion of uric acid.
  • Alter plasma solubility of uric acid.
  • Raises nor lowers serum uric acid levels.
• Reduces inflammatory response to deposited crystals.
• Colchicine is only used to treat gouty attacks.
• NSAIDs: Indometacin, Ibuprofen, Naprosyn
• Corticosteroids: Prednisone, Triamcinolone

Gout-urate-lowering therapy

• It prevents arthritis, tophi, and stones by lowering the total body pool of uric acid.
• The therapy is not indicated after the first attack, but after the second.
• Therapy initiation can worsen or bring on acute gouty arthritis.
• Gout-urate-lowering therapy is not effective in the management of acute gout because it has no anti-inflammatory activity.
• Can precipitate acute gout and can prolong gout attacks.

Comorbidities associated with Hyperuricemia

• Hyperuricemia is related to cardiovascular diseases
• Comorbidities associated with hyperuricemia:
  • Chronic kidney diseases
  • Obesity
  • Diabetes
  • Metabolic syndrome
  • Hypertension
  • Hyperlipidemia
  • Cardiovascular diseases
• Serum uric acid levels predict metabolic syndrome in patients with gout and is correlated with metabolic syndrome and diabetes.
• Uric acid can cause endothelial dysfunction and impaired nitric oxide production
• Uric acid causes tissue ischemia and microvascular diseases and nephropathies, generates oxidative stress, and causes coronary artery diseases, heart failure, and diabetes.
• Hyperuricemia is not only an effect of renal failure but also an independent risk factor for renal failure development and progression.

Uric Acid and endothelial function

• Hyperuricemia increases the effects of flow-mediated dilation, it shows us endothelial dysfunction.
• Hyperuricemic patients have lower rates, allopurinol improves in these patients the endothelial function, by decreasing uric acid levels.
• With higher levels of uric acid, STEMI and NSTEMI(myocardial infarction) increase.
• Also causes an increase in unstable angina.
• The survival rates decrease with increasing uric acid levels as shown in the hazard curve for cardiovascular death in hyperuricemia.