ANNALS O F C LIN IC A L AND LABORATORY SCIENCE, Vol. 5, No. 6 Copyright ® 1975, Institute (or Clinical Science

Etiology of

GORDON BENDERSKY, M.D.

Hahnemann Medical College and Philadelphia, PA 19102

ABSTRACT The purpose of this review is to provide a survey of the mechanisms by which hyperuricemia may occur and to acquaint the reader with the specific and nu­ merous etiologies of hyperuricemia.

Introduction Homeostatic Mechanisms The automated biochemical analysis of The level of SUA is determined by such patients undergoing routine and diagnostic factors (figure 1) as inflow of evaluations has made the uric acid precursors from dietary intake as well as (SUA) determination much more generally endogenous sources, the integrity of available. As a result, there is an increasing the outflow systems of urinary and fecal ex­ number of cases of hyperuricemia. The inci­ cretion, the volume of the extracellular com­ dence of hyperuricemia in apparently partment and probably the state of urate healthy subjects has been estimated to be binding plasma proteins. Much of the daily between 4.5 percent and 12 percent; in the production of uric acid is eliminated in gas­ overall population (including patients), the trointestinal outflow (9 to 45 percent) but incidence has become as high as 15.5 per­ there is little or no primary influence of this cent.17 The discovery in such an instance of fecal excretion in the pathogenesis of hy­ hyperuricemia has implications beyond peruricemia.14 Despite the absence of uricase merely the confirmation of the presence of in humans, uricolysis does occur in the in­ . The significance of the discovered testinal tract by bacterial degradation. hyperuricemia lies in the detection of an im­ Almost always hyperuricemia means an in­ pending hyperuricemic nephropathy, the crease in total body uric acid and the SU A is uncovering of diverse and interesting usually proportional to the size of the uric enzyme disorders, the elucidation of asso­ acid pool. As shall be seen, the usual causes ciated biochemical mechanisms of disease of hyperuricemia are overproduction or un­ and, more importantly, the potential derexcretion of uric acid or a combination of seriousness of the underlying etiology (for both. example, leukemia). The literature has been Cellular endogenous sources of uric acid reviewed to indicate that there are many include de novo synthesis, alternate mech­ different factors influencing the level of anisms of formation of purine nucleotides, SUA. The commonest of the numerous cell destruction, the various enzyme disor­ etiologies of hyperuricemia appear to be ders as well as the disorders inducing an renal failure, or lactate excess overproduction of such uric acid precursors and the use of . as adenosine monophosphate (AMP), gua-

456 ETIOLOGY OF HYPERURICEMIA 4 5 7

METABOLIC PATHS GASTROINTESTINAL + RENAL PATHS

Diet Purine De Novo Synthesis (enzyme disorders) Nucleotides Glutamine end AMP Phosphoribosylpyrophosphate GMP \ XANTHINE

Preformed nucleotides II Salvage pathway / (necrosis, myeloproliferative disease enzyme disorder^ Guaninine

Figure 1. Uric acid inflow to and outflow from the serum. nosine monophosphate (GMP) and nucleo­ ml increase at middle age;17 otherwise there sides. is no direct relationship between age and The principal outflow tract for uric acid is SUA. renal. Factors which alter renal flow, Body Weight. The SUA is approxi­ glomerular filtration, tubular reabsorption, mately 4 mg per 100 ml at 100 pounds and 6 or tubular secretion can, in one way or mg per 100 ml at 180 pounds. The Tecumseh another, adversely affect or enhance urate Health Study demonstrated a direct rela­ clearance. Uric acid is regulated in the tionship computed by regression equations.25 by bi-directional transport. About 98 percent of the uric acid filtered is reabsorbed Exercise. The SU A may rise as a result of in the ; tubular secretion is the influence of exercise36 on lactate sup­ believed to be the major route of excreted pression of urate clearance, on diminishing urate. The normal renal response to an in­ glomerular filtration and on increasing creased uric acid load is by augmented tubular reabsorption. tubular secretion, thus tending to prevent . are derived from such hyperuricemia. sources as nucleoproteins, chromosomes, Variables which normally influence the ribonucleic acids and adenosine triphos­ SU A level include: phate. Thus, guanine, hypoxanthine and Sex. Males have approximately 1 mg per xanthine coming from such sources are de­ 100 ml higher values than females and an graded to uric acid by guanase and xanthine endocrine basis for this is quite likely rather oxidase in the intestinal epithelium. The than differences in body mass.26 SUA in any one individual may vary as much Age. There is a particularly sharp rise at as 1 mg per 100 ml depending on the load of puberty and in the female an 0.8 mg per 100 preformed purines ingested. 458 BENDERSKY

Method of Laboratory Determination. specific for urate and is not affected by The difference between one method and reducing agents or chromogens. another may be as much as 1 mg per 100 ml. Alcaptonuria can cause spuriously ele­ A wide variety of phosphotungstic acid, en­ vated SUA from homogentistic acid. Inges­ zymatic, colorimetric and spectrophoto- tion of and theophylline may reduce metric procedures have been available for phosphotungstic acid and may falsely ele­ the determination of SUA.32 Because of nu­ vate the SUA level. Eliminating caffeine- merous technical variables and inherent containing beverages is not therapeutically errors, the proper interpretation of the re­ appropriate. sults requires comparing an individual value with the range of normal levels of SUA for Decreased Outflow that particular laboratory method used.5 The commonest cause of all hyper­ uricemia is renal (table I), particularly when Definition one considers the increasing number of sur­ As frequently used, the term hyper­ vivors of chronic renal disease with uricemia refers to those values of SUA ex­ . The use of diuretics and the tending beyond two standard deviations influence of and drinking alcohol on from the mean of a total population sam­ urate retention also contribute to the preva­ pled. Using the enzymatic ultraviolet spec- lence of the decreased outflow mechanisms trophotometric method, the normal adult of hyperuricemia. male SU A is 5.5 with a range of 3.1 to 7.9 mg per 100 ml. That of females is 1 mg per 100 RENAL FAILURE ml lower until after the menopause. Some In renal failure, the SUA does not usually authorities define hyperuricemia as levels rise above 10 mg per 100 ml, even in severe greater than 7.0 for men and 6.0 mg per 100 apparently because of active gas­ ml for women. trointestinal uricolysis. The hyperuricemia has been attributed to reduced glomerular Factitious Hyperuricemia filtration rate with a reduction in the filtered Drugs may produce an artifact when urate load. This hyperuricemia of renal chromogens interfere with the colorimetric insufficiency (chronic nephritis, pyelo­ technique. The automatic clinical Analyzer- nephritis, etc.) only rarely results in classic aca (Dupont copper chelate method) gout (gout occurring in one percent of exhibits falsely high levels particularly with uremics). Occasionally, hyperuricemia pre­ L-dopa, ascorbic acid, glutathione and cedes the elevation in plasma nitrogen resorcinol.21 The Technicon SMA 12-60 is in chronic renal disease, but in many patients influenced by L-dopa, ascorbic acid, the uric acid levels are not elevated to the isoniazid, alpha-methyldopa and, to a slight same degree as the urea nitrogen. In fact, extent, phenacetin. Alpha-methyldopa and markedly enhanced renal urate excretion L-dopa interfere with the phosphotungstic may be another inhibiting factor in the pre­ acid cyanide colorimetric technique. The vention of extreme hyperuricemia in chronic phosphotungstate method of Folin and Den­ renal failure; reabsorption of filtered urate nis and its many variations are the most com­ also diminishes under these circumstances.20 monly used methods for SUA determi­ Although the hyperuricemia of chronic renal nation; these can be either manual or failure is generally attributed to diminished autoanalyzer (both colorimetric). The en­ glomerular filtration, glycine uptake studies zymatic ultraviolet spectrophotometric indicate that excessive purine synthesis method of Liddle et al19 utilizing uricase is contributes to the high SU A. ETIOLOGY OF HYPERURICEMIA 4 5 9

TABLE I factor common to such hyperuricemia Etiology of Hyperuricemia etiologies as ingestion of alcohol, , ,28 following exercise, administered I. Decreased Outflow loads of acetoacetate, and beta- 1. Renal failure 2. Organic acids (lactate and ketoacids): hydroxybutyric acid, , high alcohol, starvation, diabetic acidosis, catecholamines, smoke inhalation, fat diet as well as smoke inhalation. The fructose ingestion or infusion, mechanism appears to be diminished tubular storage disease type I, branched-chain , ethylene glycol poisoning secretion when lactate, branched chain 3. Drugs: diuretics, , ethambutol, ketoacids, beta-hydroxybutyrate and aceto­ angiotensis, methoxyfluorane anesthesia and low dose , salicylate and acetate are increased. 4. Primary gout (some of the cases) When alcohol is metabolized in the liver, 5. it is converted to acetaldehyde with the aid 6. Toxemia of 7. Down's syndrome of alcohol dehydrogenase. The parallel re­ 8. Polycystic kidneys (in absence of azotemia) 9. Beryllium poisoning duction of nicotinamide adenine dinu­ 10. poisoning cleotide couples the reduction of pyruvate to

II. Increased Inflow lactate.18 The resultant excess lactate 1. Myeloproliferative diseases: leukemia, competes with urate at the tubular secretory lymphoblastoma, , multiple myeloma, myelofibrosis, megakaryocyte site. The SUA has been known to increase myelosis, non-myeloproliferative malignant from a baseline of 4 to a level of 11 mg per 2. Tissue catabolism, necrosis or excessive 100 ml with acute alcoholic intoxication, but release of nucleotides: hemolytic anemia, sickel cell anemia, immunosuppressive the trend is a twofold rise in blood lactate agents, alkylating drugs, x-ray therapy, cerebral and , and a 50 percent increase in SUA. fructose, psoriasis, heat Although starvation may lead to hyper­ 3. Increased de novo synthesis of purines: HGPRT deficiency, increased PRPP uricemia and even precipitate gout, the synthetase activity, APRT deficiency, process of slowly losing weight by type I, glutamic acid dehydrogenase, benign symmetric diminishing caloric intake (in contrast to lipomatosis, branched-chain ketoaciduria, primary gout (some cases), autism, absence complete fasting) is effective in alleviating of tears and dental dysplasia the hyperuricemia of . The plasma 4. Diet acetone of obese subjects in non-diabetic III. Miscellaneous Etiologies 1. Endocrine: , , fasting states may increase to marked levels hypoparathyroidism, hyperparathyroidism, and the SUA to more than 150 percent of nephrogenic diabetes insipidus, , •inj ections the control level; the SUA in a total fast may 2. Intoxications: barbiturates, methyl alcohol, reach 15 mg per 100 ml.24 chloroform, carbon monoxide, ammonia 3. Contracted extracellular volume: , Hyperlactic acidemia may be the im­ salt restriction, diuretics 4. Associations with unclear mechanisms: portant factor in the hyperuricemia of preg­ psychosocial factors, vitamin nancy particularly with toxemia. In addition treatment in B12 deficiency states, during labour and immediately after to this inhibition of tubular urate secretion, delivery, obesity, idiopathic hyper- the hyperuricemia of pre-eclampsia may also calciuria, Gilles de la Torette syndrome, sarcoidosis, be attributable to postural alterations, the associated changes in renal solute disposition in pregnancy20 or an enhanced activity of the renin-angiotensin system. ORGANIC ACIDS An increased concentration of aceto­ Most cases of hyperuricemia of renal acetate and betahydroxybutyrate is probably origin appear to be caused by diminished responsible for the hyperuricemia of diabetic tubular secretion of urate rather than reduc­ ketoacidosis during which the SUA may tion in glomerular filtration rate. The reach 17.6 mg per 100 ml.28 formation of organic acids appears to be a Exercise under short term exhausting con­ 4 6 0 BENDERSKY ditions may lead to lactate-induced hyper­ and the anti-tuberculous agents pyrazina- uricemia but the long term influence of exer­ mide and ethambutol increase SU A by renal cise in athletes induces a decreased SUA.4 mechanisms. The diuretics have variable Glycogen storage disease type I is due to mechanisms including volume depletion -6-phosphatase deficiency, and the (diminished extracellular compartment), high incidence of hyperuricemia and gout in stimulation of uric acid synthesis this enzyme disorder is caused by lactic- (), inhibition of tubular secre­ acidemia and/or excessive purine biosyn­ tion and enhanced reabsorption.30 In those thesis. The range of SUA levels in some patients exhibiting a -induced hype­ series is 11 to 16 mg per 100 ml. ruricemia, the increase above the pre­ Another example of an enzyme disorder treatment level has ranged from a 1 to 4 mg resulting in organic acid as a mechanism in increment. For example, patients with inducing hyperuricemia is branched chain hypertension may have a pre-treatment SUA ketonuria; classic maple syrup disease is a of 10 and then 14 mg per 100 ml after 6 days disorder of diminished ketoacid decarboxy­ of a customary dose of a diuretic (e.g. 500 lase activity manifesting retardation of mg chlorthiazide or 50 mg hydrochlorthia­ mental and motor development, convul­ zide). With discontinuation of the diuretic, sions, and short survival. Intermittent the SUA can be expected to drop to 10 mg and mild forms of this disease occur. per 100 ml within a few days. Smoke inhalation (other than cigarette Methoxyfluorane anesthesia is occa­ smoking) can elevate the SUA to 9 to 14 mg sionally associated with hyperuricemia, per 100 ml, presumably by the hypoxic probably caused by fluoride-induced dys­ stimulus to lacticacidemia.2 function of distal tubular secretion; in fact, Ethylene glycol poisoning may increase the SUA is used as the most sensitive test for SUA to 15.6 mg per 100 ml in association uncovering methoxyfluorane nephrotoxicity. with elevated levels. Forty percent of patients with beryllium HYPERTENSION poisoning develop hyperuricemia.13 This Hypertensive patients exhibit a high inci­ chemical intoxication occurs with long term dence of hyperuricemia3 (separate from the exposure to beryllium in such industries as influence of drugs and the possi­ ceramics, foundry work and fluorescent bulb bility of hyperuricemic nephropathy). Al­ manufacture. The SUA is as high as 12 mg though the specific renal mechanism has not per 100 ml. Although the exact cause for the been elucidated, reduced urate excretion diminished urate excretion is unknown, may be secondary to intrarenal circulatory hyperlacticacidemia again may be a con­ changes. A fairly direct relationship exists tributing factor. with the diastolic level in some patients.7

DRUG-INDUCED HYPERURICEMIA PRIMARY GOUT Drugs which inhibit uric acid excretion Primary gout (those idiopathic cases not include chlorthiazide, hydrochlorthiazide, considered secondary to such etiologies as , acetazolamide, ethacrynic acid, myeloproliferative diseases or diuretics) has clopamide, quinethazone, triamterene and been conceived of as deriving from an in­ bendroflumethiazide and (cata- trinsic impairment of renal urate excretion at pres). Low doses of drugs such least in some cases, estimated as 30 to 40 as probenemid, sulfinpyrazone and salicy­ percent of idiopathic gout cases. In these late, may cause urate retention.35 Other patients, an insufficient tubular secretory drugs such as angiotensin, catecholamines mechanism appears to be the fault while ETIOLOGY OF HYPERURICEMIA 46 1 purine synthesis is normal. Thus, in patients the SUA, includes sources arising from di­ with primary gout and their non-gouty rela­ etary means, neoplastic overproduction, cell tives with hyperuricemia, impaired outflow destruction characteristic of neoplasms, the alone can elevate the SUA. However, only a excessive release of purine nucleotides as a small number of gouty patients are known to result of disease processes and the increased have a specific renal lesion or known enzyme synthesis of the immediate and remote disorder. This complex subject has been ade­ precursors of uric acid. A 24-hour urinary quately reviewed by others.30 Primary gout uric acid determination is helpful in distin­ associated with increased inflow of uric acid guishing between increased production from into the serum or intracellular compartment decreased renal clearance; patients with in­ is discussed in another section. creased inflow into the serum will have a high urinary excretion, greater than 600 mg OTHER RENAL ETIOLOGIES per 24 hours in association with normal or The hyperuricemia of Down’s syndrome high urate clearance. Those with diminished may be primarily caused by diminished renal urate renal outflow will have normal to low clearance of uric acid,12 but overproduction urine urate levels despite the high SUA. of uric acid has been evident in some cases. Most of the hyperuricemic cases have only MYELOPROLIFERATIVE OVERPRODUCTION slightly higher SUA than normal, but some Among patients with gouty arthritis, as of the levels are in the 9 to 11 mg per 100 ml many as 10 percent have myeloproliferative range. disorders. These examples of secondary gout Patients with polycystic kidney have as have higher levels of SUA than those with high as a 59 percent incidence of hyper­ primary gout. Most of the hyperuricemia in uricemia as well as predisposition to gouty leukemia, lymphoblastoma, macroglobu- arthritis despite the absence of azotemia.22 linemia of Waldenstrom, polycythemia, The hyperuricemia of polycystic kidney multiple myeloma, myelofibrosis and meg- disease is not related to the conventional akaryocytic myelosis appears to derive from form of renal failure in the late stage of this the breakdown of the increased mass of condition. A genetic coexistence of poly­ nucleoprotein inherent in these hematologic cystic malformation and an unrelated hy­ disorders. Other mechanisms include in­ peruricemia is therefore suspected. creased de novo synthesis of the immediate Studies from different countries indicate purine precursors of uric acid, the response that about half of the patients with chronic to and radiation therapy in lead nephropathy have gout compared to an terms of cell lysis and further acceleration of incidence of gout of approximately 5 percent nucleic acid turnover rates, and the with renal insufficiency unassociated with infiltration of the kidney itself with leukemic lead intoxication. Saturnine gout therefore or lymphomatous cells. Uric acid excretion is appears to be a distinct entity, among the highest in acute lymphoblastic leukemia. features of which is the high SUA (up to 10 The SUA in this form of leukemia has been mg per 100 ml) with normal BUN and reported to be 44 mg per 100 ml in one .6 The hyperuricemia has been at­ patient. However, the highest known SUA tributed to defective renal excretion of was reported recently, 92 mg per 100 ml, in a urate. patient with lymphosarcoma being treated with , thioguanine and cytara- Increased Inflow bine.15 The incidence of gout in poly­ The inflow channel for uric acid, as it cythemia vera is about 10 percent. Even pertains to increasing the uric acid pool or the polycythemia of high altitude causes 4 6 2 BENDERSKY

TABLE II therapy accelerate the process of released Causes of Hyperuricemia in Malignancy purines when administered to patients with malignancy. In some series of cerebral in­ 1. Cell destruction, breakdown of nucleoprotein farction cases, 30 percent have hyper­ 2. Increased de novo synthesis of purines 3. Dehydration from anorexia uricemia.5 Similarly, a high incidence of 4. Response to chemotherapy and radiation therapy 5. Infiltration of the kidney by malignancy hyperuricemia is seen after myocardial in­ 6. Obstructive uropathy (extrinsic and intrinsic) farction. There is a controversy as to 7. Increased activity of phosphoribosylpyrophosphate synthetase whether or not the necrosis is the cause of the hyperuricemia or if the two conditions are merely co-existing genetic traits. It is be­ yond the scope of this review to discuss the hyperuricemia and the level of SUA corre­ issue of validity regarding hyperuricemia as a lates well with the patient’s . Cu­ so-called risk factor in coronary arterioscle­ riously, Hodgkin’s disease can sometimes rosis. Although more than 75 percent of gout lower the SUA by an as yet unidentified patients have , the product of tumor that enhances pathogenesis of hyperuricemia in these cases renal tubular secretion of uric acid. is obscure. In fact, in an attempt to correlate Hyperuricemia is seen in other malignant the serum uric acid with severity of coronary neoplasms such as neuroblastoma, Wilm’s lesions and angiography, it has been con­ tumor, rhabdomyosarcoma and may occur in cluded that there may not be a relationship any patient with disseminated , between SUA concentrations and coronary particularly in the more anaplastic or rapidly heart disease.1 growing tumors. There appears to be a direct Fructose ingestion in patients with con­ relationship between the incidence of hy­ genital fructose intolerance as well as in nor­ peruricemia and the mass of tumor cells, the mals can elevate the SUA by mechanisms rapidity of proliferation of neoplastic cells other than the influence of the increased and the turnover of nucleic acid. However, lactate on urate clearance. Fructose loading patients with metastatic, non-myelopro- causes a rapid degradation of preformed liferative neoplasms do not show the high purine nucleotides with the resultant levels of SUA and the uric acid nephropathy production of , hypoxanthine, as is seen in leukemia and lymphoma. xanthine and uric acid. In normals the SUA That the mechanism of hyperuricemia in may increase by 1 mg, in gout patients by 2 neoplasms (table II) may not always be the mg and in relatives of gouty patients by 2 mg release of purines from the nucleoprotein of per 100 ml. In the process of increased uric destroyed cells is suggested by at least one acid production, there is some inhibition of tumor, a hepatoma, which exhibited the de novo uric acid synthesis. While property of phosphoribosylpyrophosphate intravenous fructose and rapid ingestion of (PRPP) synthetase prompting the over­ fructose cause hyperuricemia, the ingestion production of purines. of even large loads of fructose more gradually over 24 hours in normals does not OTHER DISEASES WITH EXCESS induce hyperuricemia. RELEASE OF NUCLEOTIDES Psoriasis, a condition of accelerated Hemolytic anemias and sickle cell anemia epidermopoiesis, is associated with an in­ even in the absence of hemolysis have been creased turnover of nucleoprotein and, associated with hyperuricemia and hyperuri- hence, hyperuricemia. cosuria. Sickle cell anemia33 has a 40 percent Short term exercise has been known to incidence of hyperuricemia. Immuno-sup- elevate the SUA by virtue of the lactate in­ pressive drugs, alkylating agents and x-ray terference with tubular secretion of urates.36 ETIOLOGY OF HYPERURICEMIA 4 6 3

However, heat stress as it occurs during in­ monophosphate (IMP), and IMP is subse­ tense physical training in hot climates causes quently converted to AMP and GMP. uric acid overproduction and a high uric Underutilization of PRPP results in in­ acid excretion. Probably during the course creased concentrations of PRPP, and this of skeletal muscle injury, heat stress causes a can be a driving force in purine biosynthesis. peak hyperuricemia by the 11th day Thus, to some extent, purine synthesis de reaching levels in some cases of 12 mg per novo is controlled by the intracellular con- 100 ml.16 Although acute renal failure does centrationsof PRPP. Furthermore, when not occur, there is some nephropathy. subjected to purine overproduction, a decrease in purine synthesis will occur owing INCREASED DE NOVO SYNTHESIS to feedback inhibition of amidotransferase. OF PURINES effectively lowers the SUA In a large percentage of gout patients, probably by depleting PRPP. hyperuricemia is caused by increased rates of purine biosynthesis.34 The individual un­ DEFICIENCY OF HYPOXANTHINE GUANINE derlying enzyme disorders in some cases of PHOSPHORIBOSYL TRANSFERASE (HGPRT) primary gout are being discovered and sug­ This sex-linked enzyme disorder causing gest a heterogenous group of hyperuricemic hyperuricemia accelerates the rate of purine metabolic errors (table III). Purine over­ synthesis de novo by increasing the concen­ production appears to be possible from the tration of PRPP. HGPRT catalyzes the effects of a surplus of PRPP which by mass transfer of the phosphoribosyl moiety of action promotes the amidotransferase se­ PRPP to form nucleotides (inosinic acid and quence of biosynthesis thus: guanylic acid)23 potentially depriving the amidotransferase reaction of a purine PRPP and glutamine PRPP amidotransferase substance, PRPP (underutilization). The phosphoribosylamine deficiency of HGPRT permits a load of This is the first step programmed for purine PRPP to promote the rate-limiting amido­ synthesis. The phosphoribosylamine is then transferase reaction to accelerate. The converted by a series of enzymatic reactions specific mechanism may be that these nu­ to the parent ribonucleotide inosine- cleotides cause the small active form of the

TABLE III

Metabolic Lesions Causing Hyperuricemia

By Means o f a Surplus of Phosphoribosylpyrophosphate Promoting the In itial Step (Phosphoribosylamine Synthesis) in Purine Formation

1. Diminished activity of hypoxanthine guanine phosphoribosyl transferase (HGPRT) results in underutilization of phosphoribosylpyrophosphate (PRPP): HGPRT Hypoxanthine + PRPP ------► inosinemonophosphate (IMP) + inorganic pyrophosphate

HGPRT Guanine + PRPP ------— *■ guanosine monophosphate (GMP) + inorganic pyrophosphate

2. Greater than normal activity of PRPP synthetase results in excess PRPP:

Ribose-5-phosphate + (ATP) Svnthetase— PRPP + adenosine monophosphate (AMP) 3. Diminished activity of adenine phosphoribosyltransferase (APRT) results in underutilization of PRPP:

Adenine + PRPP — ► AMP + inorganic pyrophosphate 4 6 4 BENDERSKY amidotransferase enzyme to revert to a large OTHER ENZYME DISORDERS catalytically inactive form of amido­ Glycogen storage disease type I is transferase.11 The complete absence of associated with enhanced de novo synthesis HGPRT activity is seen in the Lesch-Nyhan possibly owing to the inability to form free syndrome. glucose, shunting sugar phosphates to The clinical features are mental retar­ ribosephosphate and then to increased PRPP dation, choreoathetosis, compulsive self- (prompted through increased hepatic hexose mutilation and aggressiveness. This may be monophosphate shunt?). SUA levels average the first instance in which a stereotyped be­ 13 mg per 100 ml. havior pattern in humans has been There is a possibility that reduced activity associated with a distinct enzyme abnor­ of glutamic acid dehydrogenase results in mality. Allegedly, every patient has bitten high intracellular glutamate thus preparing his lip destructively (unless dental extrac­ for augmented de novo purine synthesis. tions have been carried out). This disease These patients have high plasma glutamate represents the one cause of hyperuricemia and high SU A levels. with the highest rate of purine overproduc­ Benign symmetrical lipomatosis (Launois- tion (eight times more urinary uric acid than Bensaude disease) is a familial condition normal). Urate nephropathy is probably the manifesting an excessive rate of incor­ commonest cause of early . The SUA in poration of glycine into uric acid resulting in the children is usually 10 mg per 100 ml. Par­ SUA levels of 8 to 12 mg per 100 ml.10 tial deficiency states (mutants of HGPRT) of Maple syrup disease (mutants of branched this enzyme also cause hyperuricemia, sex- chain ketoaciduria) also exhibit this excessive linked (male) inheritance, a high incidence rate of de novo synthesis with analogous re­ of renal calculi and gout. sults. The fact that there are several inherited EXCESS PHOSPHORIBOSYLPYROPHOSPHATE enzyme defects supports the contention that SYNTHETASE a wide variety of primary genetic abnor­ malities are responsible for hyperuricemia Increased activity of the PRPP synthetase and gout. The vast majority of the specific enzyme is associated with the production of metabolic anomalies remain to be un­ a surplus PRPP which plays the key role in covered. the formation of the purine precursors of A case has been described with mental uric acid.34 These patients have gout with retardation, fluorescent staining of dysplastic SUA levels around 10 mg per 100 ml. This is teeth and failure to cry with tears in a three the first demonstration in man of excess year old mute, autistic boy.27 His SUA activity of a regulatory enzyme causing an ranged from 8.5 to 23.5 mg per 100 ml. His overproduction disease as a direct result of accelerated synthesis of purines de novo was mutation. revealed by a rate of conversion of glycine to uric acid seven times that of normal. There DEFICIENCY OF ADENINE was no defective activity of the HGPRT PHOSPHORIBOSYLTRANSFERASE (APRT) enzyme, but there was abnormal adeni- APRT catalyzes the transfer of the ribosyl- nephosphoribosyl transferase activity. The phosphate moiety of PRPP to adenine to specific metabolic defect remains poorly form AMP. Patients with a deficiency of understood. APRT have hyperuricemia and occasional Some gout patients are over-excretors of gout; the SUA may reach 13.4 mg per 100 uric acid and have increased xanthine oxi­ ml. dase activity four-fold greater than control ETIOLOGY OF HYPERURICEMIA 4 6 5 subjects. However, it is not known whether among gouty patients. However, hyper­ their hyperuricemia is the result of or the uricemia is associated with diminished car­ cause of the disorder or a bohydrate intolerance. Further coincidence. arises from the concept of uric acid, hyperlipemia and hyperglycemia as “ po­ DIET tential risk factors” in myocardial infarc­ tion. When one considers the numerous and The ingestion of a diet rich in purines will heterogeneous etiologies behind hyper­ increase SUA. Non-gouty patients given 4 uricemia and the speculated analogous state grams of ribonucleic acid per day exhibited of multiple etiologies in diabetes mellitus, it an increase in SUA from 4.6 to 8 and even is not surprising that the lingering dilemma 9.2 mg per 100 ml. When gouty patients are (the questioned coexistence of hyperuri­ studied, a group having an average of 9.5 mg cemia and hyperglycemia) remains unrec­ per 100 ml before any dietary change will onciled. manifest a drop to 8.4 mg per 100 ml after Injections of epinephrine can cause a rise one week of a purine-free diet.31 in the SUA with an associated increase in renal urate excretion (urate overproduc­ Miscellaneous Etiologies tion?). However, to some extent a contrary mechanism may involve that of cate- ENDOCRINE cholamine-induced hyperlacticacidemia. In hypothyroidism, repeated observations reveal that there is a higher incidence of INTOXICATIONS hyperuricemia than expected; the mech­ The hyperuricemia in severe barbiturate anism is probably renal. The SUA averages poisoning may be related to and about 7 but reaches 9 mg per 100 ml. tissue destruction. Methyl alcohol is me­ In acromegaly, the hyperuricemia has not tabolized to formic acid which may cause been specifically correlated with growth hor­ hyperuricemia through its effect on the mone activity. kidney, but the more likely mechanism is Both hypoparathyroidism and hyper­ through the seen in methyl al­ parathyroidism have associations with hy­ cohol poisoning. The hyperuricemia of peruricemia, the mechanism of which is chloroform poisoning may have either cate­ poorly understood. cholamine or direct renal mechanism. Paradoxically, some patients with nephro­ Carbon monoxide poisoning causes severe genic diabetes insipidus exhibit diminished and myocardial urate clearance despite the massive injury. The reason for hyperuricemia in am­ they have since infancy.9 These cases of con­ monia intoxication is unclear. genital, vasopressin-resistant diabetes in­ sipidus are prone to developing gouty CONTRACTED EXTRACELLULAR VOLUME arthritis. Since chlorthiazide drugs appear to This is at least the partial explanation for be the only effective antidiuretic therapy the occurrence of hyperuricemia in de­ initially for these nephrogenic cases, it is im­ hydration, salt restriction and the use of diu­ portant to realize the additional therapeutic retics. The depletion of volume would then need for allopurinol. be a pre-renal cause for hyperuricemia. Despite the structural resemblance of uric acid to the experimental diabetogen, UNCLEAR ASSOCIATIONS alloxan, there is no convincing evidence of a Numerous investigations have indicated a higher incidence of overt diabetes mellitus probable relationship between levels of SU A 4 6 6 BENDERSKY and achievement, , arduous physical may alter xanthine oxidase activity oi tasks and challenging psychological tech­ conjugated may influence tubulai niques.37 Not only is the cause of elevated reabsorption of urate. SUA in these psychosocial situations poorly Acute fatty liver of pregnancy (acute understood but apparently conflicting re­ obstetric yellow atrophy) is a rare and sults (showing a fall in SUA) may occur. usually fatal condition characterized by oc­ Explanations involving altered plasma curring in the first or second trimester, with volume and release of catecholamines have massive hepatic necrosis, coma, hyperbili­ been invoked.37 rubinemia and often . The Following the use of vitamin B12 injections pathogenesis is unknown. Although an SUA for vitamin B12 deficiency states, the SUA is of 20.6 mg per 100 ml has been reported29 in known to increase to 9 and 10 mg per 100 the absence of azotemia, usually the hy­ ml. Likewise, during labor and immediately peruricemia is mild. after delivery of the baby, hyperuricemia is a It has been estimated that the average characteristic development. biliary excretion of uric acid in normals is Obese people have a tendency toward 50 mg per day compared to approximately hyperuricemia which is intensified by star­ 200 mg per day of uric acid excreted in the vation with the risks of acute gout but which gastrointestinal tract. However, it may be is improved on a program of gradual weight speculated that the mechanism of the reduction. Although there are data sug­ possible hepatic influence on uric acid would gesting racial predominance in hyper­ more reasonably be determined by disturbed uricemia, for example Micronesians with enzyme activity than by biliary excretory SUA levels reaching 8.3 mg per 100 ml, it is means. probably more correct to attribute the hy­ peruricemia to obesity. The Chamorro popu­ Summary lation of Micronesia has a 44 percent inci­ dence of hyperuricemia among their males, Hyperuricemia is a common laboratory and there is a general association of the SUA finding with significant clinical implications. level with total daily caloric intake. It is easily detected, but its mechanisms may Idiopathic hypercalciuria has been re­ not be clearly elucidated. A scheme of ported to be associated with hyperuri­ pathogenesis has been outlined and dia­ cemia.32 Patients with the Gilles de la grammed but much is conjectural; therefore, Tourette syndrome (compulsive swearing) the classification is merely tentative. About have SUA levels in the 6 to 9 mg per 100 ml 45 diseases or categories of conditions, 20 range. In about 9 percent of sarcoidosis, mild drugs, and nine states of intoxication have hyperuricemia is said to occur, but the been surveyed. significance has been questioned.8 Hyperuricemia can be a multifactorial genetic disorder or a discrete response to a LIVER DISEASE specific stimulus. It may be governed by a A relation between the liver and gout has complex interplay of biochemical disorders been discussed for many years. Conflicting for a lifetime duration, or it may be de­ results have been observed in evaluating termined by environmental forces for a very in drinking and non­ transient course. Some conditions have both drinking gouty patients. In fact, hy- increased production of uric acid as well as pouricemia has been observed in severe al­ decreased renal outflow. For many patients, coholism and liver disease. It is speculated the underlying mechanisms have not yet that in these conditions, liver dysfunction been elucidated. ETIOLOGY OF HYPERURICEMIA 4 6 7

References 18. Lieber, C. S.: Hyperuricemia induced by alcohol. Arthritis Rheum. 8:786-796, 1965. 1. Allard, C. and Goulet, C.: Serum uric acid: not a 19. Liddle, L., Seegmiller, ]. E., and Laster, L.: The discriminator of coronary heart disease in men and enzymatic spectrophotometric method for the de­ women. Canad. Med. Assoc. J. 109:986-988, 1973. termination of uric acid. J. Lab. Clin. Med. 54:903- 2. Bergeaux, G. and Klein, R. G.: Hyperuricemia 913, 1959. following smoke inhalation. Amer. Rev. Resp. Dis. 20. Lindheimer, M. D. and Roux, J.: Role of posture in 109:145-147, 1974. sodium, water and potassium of an ab­ 3. Cannon, P. J., Stason, W. B., Demartini, F. E., normal pregnancy. Metabolism 19:619-623,1970. Sommers, S. C., and Laragh, J. H.: Hyperuricemia 21. Lum, G. and Gambino, S. R. Comparison of four in primary and renal hypertension. New Eng. J. methods for measuring uric acid. Clin. Chem. Med. 275:457-464, 1966. 19:1184-1186, 1973. 4. Cronau, L. H., Rasch, P. J., Hamby, J. W., and 22. Martinez-Maldonado, M.: Polycystic Burns, H. J.: Effects of strenuous physical training and hyperuricemia. Ann. Int. Med. 80:116-118, on SUA levels. J. Sports. Med. Phys. Fitness 12:23- 1974. 25, 1972. 23. McDonald, J. A. and Kelley, W. N.: Hypoxanthine- 5. Fessel, W. J.: Hyperuricemia in health and disease. guanine phosphoribosyltransferase deficiency. Adv. Arthritis Rheumat. 1:275-299,1972. Exp. Med. Biol. 41A.167-175, 1974. 6. Emmerson, B. T., Mirosch, W., and Douglas, J. B.: 24. Murphy, R. and Shipman, K. H.: Hyperuricemia The relative contributions of tubular reabsorption during total fasting. Arch. Int. Med. 112:192-197, and secretion to urate excretion in lead 1963. nephropathy. Aust. N. Zea. J. Med. 4:353-356, 25. Myers, A. R., Epstein, F. H., Dodge, H. J., and Mik- 1971. kelsen, W. M.: The relationship of SUA to risk fac­ 7. Goldberg, D. M., Handyside, A. J., and Winfield, tors in coronary heart disease. Amer. J. Med. D. A.: Influence of demographic factors on serum 45:520-528, 1968. concentration of seven chemical constituents in 26. Nicholls, A., Snaith, M. L., and Scott, J. T.: Effect healthy human subject. Clin. Chem. 19:395-402, of oestrogen therapy on plasma and urinary levels 1973. 8. Goldstein, R. A., Becker, K. L., Israel, H. L., and of uric acid. Brit. Med. J. 1:449-451, 1973. Moore, C. F.: Urate metabolism in sarcoidosis. 27. Nyhan, W. L., James, J. A., Teberg, A. J., Arch. Intern. Med. 133:379-381, 1974. Sweetman, L., and Nelson, L. G.: A new disorder of 9. Gorden, P., Robertson, G. L., and Seegmiller, J. E.: with behavioral manifestations. Hyperuricemia, a concomitant of congenital J. Pediat. 74:20-27, 1969. vasopressin-resistant diabetes insipidus in the adult. 28. Padova, J. and Bendersky, G.: Hyperuricemia in New Eng. J. Med. 284:1057-1060, 1971. . New Eng. J. Med. 267:530- 10. Greene, M. L., Glueck, C. J., Fujimoto, W. Y., and 534, 1962. Seegmiller, J. E.: Benign symmetric lipomatosis 29. Quigley, M. M.: Acute obstetric yellow atrophy (Launois-Bensaude adenolipomatosis) with gout presenting as idiopathic hyperuricemia. South. and hyperlipoproteinemia. Amer. J. Med. 48:239- Med. J. 67:142-144, 1974. 246, 1970. 30. Rieselbach, R. E. and Steele, T. H.: Influence of the 11. Holmes, E. W., Wyngaarden, J. B., and Kelley, kidney upon urate homeostasis in health and W. N.: Human glutamic PRPP amidotransferase. disease. Amer. J. Med. 56:665-674, 1974. Adv. Exp. Med, Biol. 41A:43-53, 1974. 31. Seegmiller, J. E., Grayzal, A. I., Laster, L., and Lid­ 12. Howell, A., Mason, A. S., Brown, E., Watts, dle, L.: Uric acid production in gout. J. Clin. Invest. R. W. E., Chanarin, I., McPherson, K., and Ridler, 40:1304-1314, 1961. M. A. C.: Red cell size and uric acid in Down’s syn­ 32. Seegmiller, J. E.: Diseases of purine and pyrimidine drome. Scand. J. Haemat. 11:140-147, 1973 metabolism. Duncan’s Diseases of Metabolism. 13. Kelley, W. N., Goldfinger, S.E., and Hardy, H. L.: Bondy, P. K. and Rosenberg, E. F., eds. Hyperuricemia in chronic beryllium disease. Ann. Philadelphia, W. B. Saunders Co., pp. 655-773, Int. Med. 70:977-983, 1969. 1974. 14. Kelley, W. N., Grobner, W., and Holmes, E.: Cur­ 33. Walker, B. R. and Alexander, F.: Hyperuricemia in rent concepts in the pathogenesis of hyperuricemia. sickle cell anemia. JAMA 215:255-258, 1971. Metabolism 22:939-954, 1973. 34. Wyngaarden, J. B.: Metabolic defects of primary 15. Kjellstrand, C. M., Campbell, D. C., von Har- hyperuricemia and gout. Amer. J. Med. 56:651-664, titzsch, B., and Buselmeier, T. J.: Hyperuricemic 1974. acute renal failure. Arch. Int. Med. 133:349-359, 35. Yü, T.: Milestones in the treatment of gout. Amer. 1974. 16. Knöchel, J. P., Dotin, L. N., and Hamburger, R. J.: J. Med. 56:676-685, 1974. Heat stress, exercise and muscle injury: Effects on 36. Zachau-Christiansen, B.: The rise in SUA during urate metabolism and renal function. Ann. Int. muscular exercise. Scand. J. Clin. Lab. Invest. Med. 81:321-328,1974. 11:57-60, 1959. 17. Laing, J. K. and Murray, J. T.: Serum uric acid 37. Zir, L. M., McHugh, W. B., Rahe, R. H., Arthur, levels in New Zealanders. N. Zea. Med. J. 78:65-67, R. J., and Rubin, R. T.: Renal excretion of uric acid. 1973. Arch. Intern. Med. 132:808-812, 1974.