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Case study- Gout
A 46-year-old male presented to the emergency department with severe right toe pain. The patient was in usual state of health until early in the morning when he woke up with severe pain in his right big toe. The patient denied any trauma to the toe and no previous history of such pain in other joints. He did say that he had a “few too many” beers with the guys last night. Patient’s past medical history was significant for hypertension, diabetes mellitus, chronic Alcoholism and renal stones for which he underwent left nephrectomy about 25 years ago. Family history was non-contributory.
On examination, he was found to have a temperature of 38.2°C (100.8°F) and in moderate distress secondary to the pain in his right toe. The right big toe was swollen, warm, red, and exquisitely tender. The remainder of the examination was normal. Synovial fluid was obtained and revealed rod- or needle-shaped crystals that were negatively birefringent under polarizing microscope. The laboratory investigation report revealed;
Hemoglobin – 8.9gm/dl,
ESR -124 mm at the end of first hour,
Leucocyte count -7400/cmm with normal differential count
Random blood sugar-139 mg/dl
Creatinine- 1.6 mg/dl
Serum uric acid level- 10.9 mg/dl
His 24 hour urinary uric acid excretion was 446 mg/dl.
Serum calcium, phosphorus, LFT, electrolytes and lipid profile were normal.
What is the likely diagnosis?
How would you make a definite diagnosis?
What is the Pathophysiology of this disorder?
The patient is suffering from Gouty Arthritis. The patient reported with pain in the big toe. Pain in the big toe precipitated by alcohol is very typical of history of gout. The patient had past history of alcoholism and renal stones. High serum urate levels and synovial fluid analysis are diagnostic of gout.
Gout is a metabolic disease most often affecting middle-aged to elderly men and postmenopausal women. It is the result of an increased body pool of urate with hyperuricemia. It is typically characterized by episodic acute and chronic arthritis, due to deposition of Mono Sodium Urate crystals in joints and connective tissues with the risk for deposition in kidney interstitium or uric acid nephrolithiasis.
Acute arthritis is initially monarticular and often involves the first metatarsophalangeal joint. Symptoms include acute pain, tenderness, warmth, redness, and swelling.
Diagnosis requires identification of crystals in synovial fluid. Treatment of acute attacks is with anti-inflammatory drugs. The frequency of attacks can be reduced by regular use of NSAIDs, colchicine, or both and by treating hyperuricemia with Allopurinol or uricosuric drugs.
Uric acid is the final breakdown product of purine degradation in humans.
Purine bases are used in many important biological processes including the formation of nucleic acids (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]), energy currency (adenosine triphosphate [ATP]), cofactors (nicotinamide adenine dinucleotide [NAD], flavin adenine dinucleotide [FAD]), and cellular signalling (cAMP and cGMP). Purines are both synthesized de novo and taken in through the diet. Their degradation is a ubiquitous process; however, increased levels of the enzymes that carry out the metabolism of purine bases suggest that purine catabolism is higher in the liver and the gastrointestinal tract. Abnormalities in purine biosynthesis and degradation are associated with numerous disorders suggesting that the regulation of purine levels is essential.
Degradation of purine nucleotides, nucleosides and bases follow a common pathway. During purine catabolism, the purine nucleotides
Figure-1 showing purine nucleotide catabolism.
Adenosine monophosphate (AMP) and GMP are generated from the dephosphorylation of ATP and GTP, respectively. AMP is then deaminated to IMP by AMP deaminase. Subsequently, GMP and IMP are dephosphorylated by specific 5’Nucleotidase to produce the nucleosides guanosine and Inosine respectively.
Alternatively, AMP can be dephosphorylated to form adenosine, which is then deaminated by adenosine deaminase (ADA) to form Inosine. Inosine and guanosine are further broken down by the cleavage of the purine base from the ribose sugar to yield ribose 1-phosphate and hypoxanthine and guanine, respectively. Similar reactions are carried out for the degradation of purine deoxy Ribonucleotides and deoxyribonucleoside. Guanine is deaminated to form Xanthine, whereas hypoxanthine is oxidized to form Xanthine by the enzyme Xanthine oxidase. Xanthine is further oxidized, again by Xanthine oxidase, to form uric acid, which is excreted in the urine.
Uric acid has a pKa of 5.4 and is in the ionized urate form at physiologic pH. Urate is not very soluble in an aqueous environment and the concentration of urate in human blood is very close to saturation. Therefore, conditions that lead to excessive degradation of purine bases can lead to the formation of urate crystals.
Hyperuricemia can result from increased production or decreased excretion of uric acid or from a combination of the two processes. Sustained hyperuricemia predisposes some individuals to develop clinical manifestations including gouty arthritis, urolithiasis, and renal dysfunction.
Hyperuricemia is defined as a plasma (or serum) urate concentration >408 mol/L (6.8 mg/dL). The risk of developing gouty arthritis or urolithiasis increases with higher urate levels and escalates in proportion to the degree of elevation.
Hyperuricemia is present in between 2.0 and 13.2% of ambulatory adults and is even more frequent in hospitalized individuals.
Causes of Hyperuricemia
Hyperuricemia may be classified as primary or secondary depending on whether the cause is innate or is the result of an acquired disorder. However, it is more useful to classify hyperuricemia in relation to the underlying pathophysiology, i.e., whether it results from increased production, decreased excretion, or a combination of the two.
A) Increased Urate Production-
The common causes are as follows-
1) Diet contributes to the serum urate in proportion to its purine content. Foods high in nucleic acid content include liver, “sweetbreads” (i.e., thymus and pancreas), kidney, and anchovy. Excessive consumption leads to hyperuricemia.
2) Endogenous sources of purine production also influence the serum urate level. De novo purine biosynthesis is an 11-step process that forms Inosine monophosphate (IMP). The rates of purine biosynthesis and urate production are determined, for the most part, by amidotransferase, which combines phosphoribosylpyrophosphate (PRPP) and glutamine. Metabolic abnormalities that lead to the overproduction of purine nucleotides through the de novo pathway lead to increased purine degradation and subsequent hyperuricemia. An example of this is an increase in the activity of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase. This enzyme is responsible for the production of PRPP, which is an important precursor of both purine and pyrimidine de novo biosynthesis. Elevations in PRPP lead to increased purine nucleotide production that can in turn increase the rate of degradation and hence increased uric acid production. Similarly increased activity of amidotransferase also leads to similar effects of increased uric acid production.
3) Hyperuricemia can also result from defects in the purine salvage pathway. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is responsible for reforming IMP and GMP from hypoxanthine and guanine, respectively. In this manner purine bases are salvaged back into the purine nucleotide pool. Lesch-Nyhan syndrome results from an inherited deficiency in HGPRT. This syndrome is associated with mental retardation and self-destructive behavior, which may be associated with inadequate production of purine nucleotides through the salvage pathway in certain neuronal cells. In addition, Lesch-Nyhan patients have gout resulting from the inability to salvage purine bases, which leads to increased levels of uric acid.
4) Over production of urate may also be due to glucose-6-phosphatase deficiency (von Gierke disease) , In von Gierke disease its both overproduction and decreased excretion responsible for hyperuricemia. Overproduction is due to over active HMP pathway to utilize the excess load of glucose-6 phosphate and decreased excretion is due to lactate accumulation as a result of anaerobic Glycolysis in muscles. Lactate is excreted while uric acid reabsorbed through anion exchange transporters.
5) Accelerated purine nucleotide degradation can also cause hyperuricemia, i.e., with conditions of rapid cell turnover, proliferation, or cell death, as in leukemia, Cytotoxic therapy for malignancy, hemolysis, or rhabdomyolysis.
6) Overproduction of uric acid may also occur, hemolytic anemias, pernicious anemia, ineffective erythropoiesis (as in B-12 deficiency) and obesity.
B) Decreased Uric Acid Excretion
Over 90% of individuals with sustained hyperuricemia have a defect in the renal handling of uric acid.
Common causes of secondary gout due to under excretion of uric acid include-
· Primary idiopathic
· Renal insufficiency
· Polycystic kidney disease
· Diabetes insipidus
· Lactic acidosis
· Diabetic ketoacidosis
· Starvation ketosis
· Lead intoxication
· Toxemia of pregnancy
· Down syndrome
· Low dose salicylates
· Nicotinic acid
C) Combined Mechanism
· Glucose- 6 phosphatase deficiency
Alcohol promotes hyperuricemia because of increased urate production and decreased uric acid excretion. Excessive alcohol consumption accelerates hepatic breakdown of ATP to increase urate production. Alcohol consumption can also induce hyperlacticacidemia, which blocks uric acid secretion. The higher purine content in some alcoholic beverages such as beer may also be a factor.
Decreased renal excretion is by far the most common cause of hyperuricemia.
Urate precipitates as needle-shaped monosodium urate (MSU) crystals, which are deposited extracellularly in cartilage tendons, tendon sheaths, ligaments, walls of bursae and skin around cooler distal joints and tissues (eg, ears). In severe, long-standing hyperuricemia, MSU crystals may be deposited in larger central joints and in the parenchyma of organs such as the kidney. At the acid pH of urine, urate precipitates readily as small plate like or irregular crystals that may aggregate to form gravel or stones, which may cause obstruction. Tophi are MSU crystal aggregates that most often develop in joint and cutaneous tissue.
Symptoms and Signs
Acute gouty arthritis usually begins with sudden onset of pain (often nocturnal). The metatarsophalangeal joint of a great toe is most often involved, but the ankle, knee, wrist, and elbow are also common sites. Rarely, the hip, shoulder, sacroiliac, sternoclavicular, or cervical spine joints are involved. The pain becomes progressively more severe, usually over a few hours, and is often excruciating. Swelling, warmth, redness, and exquisite tenderness may suggest infection. The overlying skin may become tense, warm, shiny, and red or purplish. Fever, tachycardia, chills, and malaise sometimes occur. Coexisting hypertension, hyperlipidemia, and obesity are common.
Course: The first few attacks usually affect only a single joint and last only a few days. Later attacks may affect several joints simultaneously or sequentially and persist up to 3 wk if untreated. Subsequent attacks develop after progressively shorter symptom-free intervals. Eventually, several attacks may occur each year.
Tophi: They are usually firm yellow or white papules or nodules, single or multiple. They can develop in various locations, commonly the fingers, hands, feet, and around the olecranon or Achilles tendon. Tophi can also develop in the kidney and other organs and under the skin on the ears. Tophi may even erupt through the skin, discharging chalky masses of urate crystals. Tophi may eventually cause deformities.
Chronic gout: Chronic gouty arthritis can cause pain, deformity, and limited joint motion. Inflammation can be flaring in some joints while subsiding in others. About 20% of patients with gout develop urolithiasis with uric acid stones or Ca oxalate stonese. Untreated progressive renal dysfunction, most often related to coexisting hypertension or, less often, some other cause of nephropathy, further impairs excretion of urate, accelerating crystal deposition in tissues.
Cardiovascular disease and the metabolic syndrome are common among patients with gout.
i) Diagnosis of Acute gouty arthritis
- Clinical criteria
- Synovial fluid analysis
- Serum uric acid level
Gout should be suspected in patients with acute single joint involvement, particularly older adults or those with other risk factors.
Synovial fluid analysis: Synovial fluid analysis can confirm the diagnosis by identifying needle-shaped, strongly negatively birefringent urate crystals that are free in the fluid or engulfed by phagocytes.
Serum urate level: An elevated serum urate level supports the diagnosis of gout but is neither specific nor sensitive; at least 30% of patients have normal serum urate at the time of an acute attack. However, the serum urate level reflects the size of the extracellular miscible urate pool. The level should be measured on 2 or 3 occasions in patients with newly proven gout to establish a baseline; if elevated (> 7 mg/dL [> 0.41 mmol/L]), 24-h urinary urate excretion can also be measured. Normal 24-h excretion is about 600 to 900 mg on a regular diet. Quantification of urinary uric acid can indicate whether hyperuricemia results from impaired excretion or increased production and help guide any serum urate–lowering therapy. Patients with elevated urine excretion of urate are at increased risk of urolithiasis.
X-rays: X‑rays of the affected joint may be taken to look for bony tophi but are probably unnecessary if the diagnosis has been established by synovial fluid analysis.
ii) Diagnosis of chronic gouty arthritis: Chronic gouty arthritis should be suspected in patients with persistent joint disease or subcutaneous or bony tophi. Plain x‑rays of the first metatarsophalangeal joint or other affected joint may be useful. Bony lesions are not specific or diagnostic but nearly always precede the appearance of subcutaneous tophi.
With early diagnosis, therapy enables most patients to live a normal life. Gout is generally more severe in patients whose initial symptoms appear before age 30.
- Termination of an acute attack with NSAIDs(Non steroidal anti inflammatory drugs) or corticosteroids
- Prevention of recurrent acute attacks with daily colchicine or an NSAID
- Prevention of further deposition of MSU crystals and resolution of existing tophi by lowering the serum urate level
- Treatment of coexisting hypertension, hyperlipidemia, and obesity.
Lowering the serum urate level:
Neither colchicine, NSAIDs, nor corticosteroids, retard the progressive joint damage caused by tophi. Such damage can be prevented and, if present, reversed with urate-lowering drugs. Tophaceous deposits are resorbed by lowering serum urate. Lowering serum urate may also decrease the frequency of acute arthritic attacks. This decrease is accomplished by
- Blocking urate production with allopurinol
- Increasing urate excretion with a uricosuric drug
- Using both types of drugs together in severe tophaceous gout
Uricase can also be used but not yet routinely. Uricase is an enzyme that converts urate to allantoin, which is more soluble.
· Fluid intake ≥ 3 L/ day is desirable for all patients, especially those who chronically pass urate gravel or stones.
· Alkalinization of urine (with K citrate, or acetazolamide) is also occasionally effective for those with persistent uric acid urolithiasis despite Hypouricemic therapy and adequate hydration.
· Extracorporeal shock wave lithotripsy may be needed to disintegrate renal stones.
· Large tophi in areas with healthy skin may be removed surgically.
· Dietary restriction of purines is less effective, but high intake of high-purine food and alcohol (beer in particular) should be avoided.
· Carbohydrate restriction and weight loss can lower serum urate in patients with insulin resistance because high insulin levels suppress urate excretion.