3246 PART 12 Endocrinology and Metabolism

■ VARIEGATE PORPHYRIA

VP is an autosomal dominant hepatic porphyria that results from the

deficient activity of PROTO-oxidase, the seventh enzyme in the heme

biosynthetic pathway, and can present with neurologic symptoms,

photosensitivity, or both. VP is particularly common in South Africa,

where 3 of every 1000 whites have the disorder. Most are descendants

of a couple who emigrated from the Netherlands to South Africa in

1688. In other countries, VP is less common than AIP. Rare cases of

homozygous dominant VP, presenting in childhood with cutaneous

symptoms, also have been reported.

Clinical Features VP can present with skin photosensitivity, acute

neurovisceral crises, or both. In two large studies of VP patients, ~60%

had only skin lesions, 20% had only acute attacks, and ~20% had both.

Acute attacks are identical to those in AIP and are precipitated by the

same factors as AIP (see above). Blistering skin manifestations are

similar to those in PCT but are more difficult to treat and usually are

of longer duration. Homozygous VP is associated with photosensitivity, neurologic symptoms, and developmental disturbances, including

growth retardation, in infancy or childhood; all cases had increased

erythrocyte levels of zinc protoporphyrin, a characteristic finding in all

homozygous porphyrias so far described.

Diagnosis Urinary ALA and PBG levels are increased during acute

attacks but may return to normal more quickly than in AIP. Increases

in fecal protoporphyrin and COPRO III and in urinary COPRO III are

more persistent. Plasma porphyrin levels also are increased, particularly when there are cutaneous lesions. VP can be distinguished rapidly

from all other porphyrias by examining the fluorescence emission

spectrum of porphyrins in plasma since VP has a unique fluorescence

peak at neutral pH.

Assays of PROTO-oxidase activity in cultured fibroblasts or lymphocytes are not widely available. Over 205 mutations have been

identified in the PPOX gene from unrelated VP patients (Human Gene

Mutation Database; www.hgmd.org). The missense mutation R59W

is the common mutation in most South Africans with VP of Dutch

descent. Five missense mutations were common in English and French

VP patients; however, most mutations have been found in only one or

a few families.

TREATMENT

Variegate Porphyria

Acute attacks are treated as in AIP, and hemin should be started

early in most cases. Givosiran has proven effective in clinical trials

for patients with recurrent attacks. Other than avoiding sun exposure, there are few effective measures for treating the skin lesions.

β-Carotene, phlebotomy, and chloroquine are not helpful.

THE ERYTHROPOIETIC PORPHYRIAS

In the erythropoietic porphyrias, excess porphyrins from bone marrow

erythrocyte precursors are transported via the plasma to the skin and

lead to cutaneous photosensitivity.

■ X-LINKED SIDEROBLASTIC ANEMIA

XLSA results from the deficient activity of the erythroid form of

ALA-synthase (ALA-synthase 2) and is associated with ineffective erythropoiesis, weakness, and pallor.

Clinical Features Typically, males with XLSA develop refractory

hemolytic anemia, pallor, and weakness during infancy. They have

secondary hypersplenism, become iron overloaded, and can develop

hemosiderosis. The severity depends on the level of residual erythroid

ALA-synthase activity and on the responsiveness of the specific mutation to pyridoxal 5′-phosphate supplementation (see below). Peripheral

blood smears reveal a hypochromic, microcytic anemia with striking

anisocytosis, poikilocytosis, and polychromasia; the leukocytes and

platelets appear normal. Hemoglobin content is reduced, and the mean

corpuscular volume and mean corpuscular hemoglobin concentration

are decreased. Patients with milder, later-onset disease have been

reported recently.

Diagnosis Bone marrow examination reveals hypercellularity with

a left shift and megaloblastic erythropoiesis with an abnormal maturation. A variety of Prussian blue–staining sideroblasts are observed.

Levels of urinary porphyrin precursors and of both urinary and fecal

porphyrins are normal. The activity of erythroid ALA-synthase 2 is

decreased in bone marrow, but this enzyme is difficult to measure in

the presence of the normal ALA-synthase 1 housekeeping enzyme.

Definitive diagnosis requires the demonstration of loss-of-function

mutations in the erythroid ALAS2 gene, of which >110 have been

identified.

Treatment The severe anemia may respond to pyridoxine supplementation. This cofactor is essential for ALA-synthase activity, and

mutations in the pyridoxine binding site of the enzyme have been

found in several responsive patients. Cofactor supplementation may

make it possible to eliminate or reduce the frequency of transfusions.

Unresponsive patients may be transfusion dependent and require

chelation therapy.

■ CONGENITAL ERYTHROPOIETIC PORPHYRIA

CEP, also known as Günther’s disease, is an autosomal recessive disorder. It is due to the markedly deficient, but not absent, activity of

URO-synthase and the resultant accumulation of URO I and COPRO

I isomers. CEP is associated with hemolytic anemia and cutaneous

lesions.

Clinical Features Severe cutaneous photosensitivity typically

begins from birth. The skin over light-exposed areas is friable, and

bullae and vesicles are prone to rupture and infection. Skin thickening,

focal hypo- and hyperpigmentation, and hypertrichosis of the face and

extremities are characteristic. Secondary infection of the cutaneous

lesions can lead to disfigurement of the face and hands. Porphyrins

are deposited in teeth and in bones. As a result, the teeth are brownish

and fluoresce on exposure to long-wave ultraviolet light. Hemolysis

is due to the marked increase in erythrocyte porphyrins and leads to

splenomegaly. Adults with a milder later-onset form of the disease also

have been described.

Diagnosis URO and COPRO (mostly type I isomers) accumulate

in the bone marrow, erythrocytes, plasma, urine, and feces. The predominant porphyrin in feces is COPRO I. The diagnosis of CEP can

be confirmed by demonstration of markedly deficient URO-synthase

activity and/or by the identification of specific mutations in the UROS

gene. The disease can be detected in utero by measuring porphyrins

in amniotic fluid and URO-synthase activity in cultured amniotic

cells or chorionic villi or by the detection of the family’s specific gene

mutations. Molecular analyses of the mutant alleles from unrelated

patients have revealed the presence of >55 mutations in the UROS gene,

including six in the erythroid-specific promoter of the UROS gene.

Genotype/phenotype correlations can predict the severity of the disease. The CEP phenotype may be modulated by sequence variations in

the erythroid-specific ALA-synthase 2, the mutation of which typically

causes XLP. One mutation (p.ArgR216WTrp) in GATA1, encoding the

X-linked erythroid-specific transcription factor GATA binding protein

1 (GATA1), has been identified in an individual with CEP, thrombocytopenia, and β thalassemia.

TREATMENT

Congenital Erythropoietic Porphyria

Severe cases often require transfusions for anemia. Chronic transfusions of sufficient fresh packed erythrocytes to suppress erythropoiesis are effective in reducing porphyrin production but result

in iron overload. Splenectomy may reduce hemolysis and decrease

transfusion requirements. Protection from sunlight and from minor

skin trauma is important. Complicating bacterial infections should

be treated promptly. Recently, non-transfusion-dependent patients

3247The Porphyrias CHAPTER 416

have been treated by periodic phlebotomies to decrease iron levels,

thereby decreasing erythropoiesis and porphyrin accumulation.

This approach has not been evaluated in clinical trials to date. Bone

marrow and cord blood transplantation has proven curative in

transfusion-dependent children, providing the rationale for stem

cell gene therapy.

■ ERYTHROPOIETIC PROTOPORPHYRIA

EPP is an autosomal recessive disorder resulting from the deficient

activity of FECH, the last enzyme in the heme biosynthetic pathway.

EPP is the most common erythropoietic porphyria in children and,

after PCT, the second most common porphyria in adults. EPP patients

have FECH activities as low as 15–25% of normal in lymphocytes and

cultured fibroblasts. Protoporphyrin IX accumulates in bone marrow

reticulocytes and circulating erythrocytes, is released into the plasma,

and then is taken up in the liver where it is excreted in the bile and feces.

Plasma protoporphyrin IX taken up by the vascular cells in the skin

is photoactivated on exposure to sunlight causing phototoxic cellular

damage and excruciatingly painful nonblistering phototoxicity. In most

symptomatic patients (>95%) with this disorder, a deleterious mutation

in one FECH allele was inherited with the relatively common (~10% of

Caucasians) intronic 3 (IVS3) alteration (IVS3–48T>C) on the other

allele that results in the low expression of the normal enzyme. In ~2% of

EPP families, two FECH deleterious mutations have been found.

XLP is a less common condition with the same phenotype in

affected males, including increased erythrocyte protoporphyrin IX

levels resulting from gain-of-function mutations in the last exon of

the erythroid-specific form of 5-aminolevulinate-synthase 2 (ALAS2).

These mutations delete or alter the ALAS2 C-terminal amino acids

resulting in its increased activity and the subsequent accumulation

of protoporphyrin IX. Manifestations in female heterozygotes with

XLP can range from asymptomatic to as severe as their affected male

relatives. The variation in the presence and severity of manifestations

in XLP heterozygotes results primarily from random X-chromosomal

inactivation. XLP accounts for ~2–10% of cases with the EPP phenotype in Europe and North America. Rare patients with EPP symptoms

and elevated erythrocyte protoporphyrin IX levels do not have mutations in FECH or ALAS2 on genetic testing. In an affected family with

EPP symptoms and accumulation of protoporphyrin IX, an autosomal

dominant mutation was found in human CLPX, a modulator of heme

biosynthesis.

Clinical Features In EPP and male XLP patients, skin photosensitivity, which differs from that in other cutaneous porphyrias, usually

begins in early childhood. The initial symptoms on sun exposure

consist of tingling, stinging, itching, or heat/burning sensations on the

exposed skin occurring within <10 to 30 min of exposure in >60% of

patients; most will have these prodromal symptoms within an hour of

sun exposure. The prodromal symptoms are the “warning signal” to

get out of the sun, thereby avoiding a severe incapacitating painful

attack that can last from 2–5 days. Photosensitivity is associated with

substantial elevations in erythrocyte protoporphyrin IX and occurs

only in patients with genotypes that result in FECH activities below

~35% of normal. Vesicular lesions are uncommon. Redness and swelling develop after prolonged sun exposure and resemble angioedema

(Fig. 416-4). Pain symptoms may seem out of proportion to the visible

skin involvement. Chronic skin changes may include lichenification,

leathery pseudovesicles, labial grooving, and nail changes. Severe

scarring is rare, as are pigment changes, friability, and hirsutism. Unless

hepatic or other complications develop, protoporphyrin IX levels and

symptoms of photosensitivity tend to remain remarkably stable over

many years in most patients. Factors that exacerbate the hepatic porphyrias play no role in EPP or XLP.

The primary source of excess protoporphyrin is the bone marrow

erythroid cells. Erythrocyte protoporphyrin IX is free (not complexed

with zinc) and is mostly bound to hemoglobin. In plasma, protoporphyrin IX is bound to albumin. Hemolysis and anemia are absent or

usually mild.

Although EPP is an erythropoietic porphyria, up to 27% of EPP

patients may have minor abnormalities of liver function, and in ~2–5%

of these patients, the accumulation of protoporphyrins causes chronic

liver disease that can progress to liver failure requiring transplantation.

Protoporphyrin IX is insoluble, and excess amounts form crystalline

structures in liver cells (Fig. 416-4) and can decrease hepatic bile flow.

Studies in the mouse model of EPP have shown that the bile duct epithelium may be damaged by toxic bile, leading to biliary fibrosis. Thus,

rapidly progressive liver disease appears to be related to the cholestatic

effects of protoporphyrins and is associated with increasing hepatic

protoporphyrin IX levels due to impaired hepatobiliary excretion and

increased photosensitivity. The hepatic complications also are often

characterized by increasing levels of protoporphyrins in erythrocytes

and plasma as well as severe abdominal and back pains, especially in

the right upper quadrant. Gallstones composed at least in part of protoporphyrin IX occur in some patients. Hepatic complications appear

to be higher in EPP due to two pathogenic FECH mutations and in

males with XLP.

Diagnosis A substantial increase in erythrocyte protoporphyrin IX,

which is predominantly free and not complexed with zinc, is the hallmark of EPP. Protoporphyrin levels also are variably increased in bone

marrow, plasma, bile, and feces. Erythrocyte protoporphyrin IX concentrations are increased in other conditions such as lead poisoning, iron

deficiency, various hemolytic disorders, all homozygous forms of other

porphyrias, and sometimes even in acute porphyrias. In all these conditions, however, in contrast to EPP, protoporphyrin IX is complexed

with zinc. Therefore, after an increase in erythrocyte protoporphyrin

IX is found in a suspected EPP patient, it is important to confirm the

diagnosis by an assay that distinguishes free and zinc-complexed protoporphyrin. Erythrocytes in EPP also exhibit red fluorescence under

fluorescence microscopy at 620 nm. Urinary levels of porphyrins and

porphyrin precursors are normal. FECH activity in cultured lymphocytes or fibroblasts is decreased (<30% of normal mean). DNA diagnosis by mutation analysis is recommended to detect the causative FECH

mutation(s) and/or the presence of the IVS3–48T>C low expression

allele. To date, >220 mutations have been identified in the FECH gene,

many of which result in an unstable or absent enzyme protein (null

alleles) (Human Gene Mutation Database; www.hgmd.org).

In XLP, the erythrocyte protoporphyrin levels appear to be higher

than in EPP, and the proportions of free and zinc protoporphyrin IX

may reach 50%. XLP accounts for ~2% of patients with the EPP phenotype in Western Europe. Recent studies show that ~10% of North

American patients with the EPP phenotype have XLP.

FIGURE 416-4 Erythema and edema of the hands due to acute photosensitivity in a

10-year-old boy with erythropoietic protoporphyria. (Reproduced with permission

from P Poblete-Gutiérrez et al: The porphyrias: clinical presentation, diagnosis and

treatment. Eur J Dermatol 16:230, 2006.)

3248 PART 12 Endocrinology and Metabolism

Purines (adenine and guanine) and pyrimidines (cytosine, thymine,

uracil) serve fundamental roles in the replication of genetic material,

gene transcription, protein synthesis, and cellular metabolism. Disorders that involve abnormalities of nucleotide metabolism range from

relatively common diseases such as hyperuricemia and gout, in which

there is increased production or impaired excretion of a metabolic end

product of purine metabolism (uric acid), to rare enzyme deficiencies

that affect purine and pyrimidine synthesis or degradation. Understanding these biochemical pathways has led, in some instances, to the

development of specific forms of treatment, such as the use of allopurinol and febuxostat to reduce uric acid production.

URIC ACID METABOLISM

Uric acid is the final breakdown product of purine degradation in

humans. It is a weak diprotic acid with pKa

 values of 5.75 and 10.3.

Urates, the ionized forms of uric acid, predominate in plasma, extracellular fluid, and synovial fluid, with ~98% existing as monosodium

urate at pH 7.4.

Plasma is saturated with monosodium urate at a concentration of

405 μmol/L (6.8 mg/dL) at 37°C. At higher concentrations, plasma

is therefore supersaturated—a situation that creates the potential for

urate crystal precipitation. However, plasma urate concentrations can

reach 4800 μmol/L (80 mg/dL) without precipitation, perhaps because

of the presence of solubilizing substances.

The pH of urine greatly influences the solubility of uric acid. At pH

5.0, urine is saturated with uric acid at concentrations ranging from

360 to 900 μmol/L (6–15 mg/dL). At pH 7.0, saturation is reached at

concentrations from 9840 to 12,000 μmol/L (158–200 mg/dL). Ionized

forms of uric acid in urine include monosodium, disodium, potassium,

ammonium, and calcium urates.

Although purine nucleotides are synthesized and degraded in all

tissues, urate is produced only in tissues that contain xanthine oxidase,

primarily the liver and small intestine. Urate production varies with the

purine content of the diet and with rates of purine biosynthesis, degradation, and salvage (Fig. 417-1). Normally, two-thirds to three-fourths

417 Disorders of Purine and

Pyrimidine Metabolism

John N. Mecchella, Christopher M. Burns

Nucleotides

Nucleosides

Bases

Urate

Urine Intestine

Tophi

Diet

Nucleic acids

pathways

De novo biosynthesis

Salvage

FIGURE 417-1 The total-body urate pool is the net result between urate production

and excretion. Urate production is influenced by dietary intake of purines and the

rates of de novo biosynthesis of purines from nonpurine precursors, nucleic acid

turnover, and salvage by phosphoribosyltransferase activities. The formed urate is

normally excreted by urinary and intestinal routes. Hyperuricemia can result from

increased production, decreased excretion, or a combination of both mechanisms.

When hyperuricemia exists, urate can precipitate and deposit in tissues as tophi.

TREATMENT

Erythropoietic Protoporphyria

Avoiding sunlight exposure and wearing clothing designed to provide protection for conditions with chronic phototoxicity are essential. Various other treatments, including oral β-carotene, have proven

of little benefit. Afamelanotide, an α-melanocyte-stimulating hormone (MSH) analogue that stimulates tanning, has been approved

for the treatment of EPP and XLP in the European Union by the

European Medicines Agency and in the United States by the U.S.

Food and Drug Administration. Dersimelagon, an orally administered, small-molecule, selective melanocortin-1 receptor (MC1R)

agonist that increases skin melanin without sun exposure, is currently in phase 3 clinical trials for EPP and XLP.

Treatment of hepatic complications, which may be accompanied by motor neuropathy, is difficult. Cholestyramine and other

porphyrin absorbents such as activated charcoal may interrupt the

enterohepatic circulation of protoporphyrin and promote its fecal

excretion, leading to some improvement. Plasmapheresis and intravenous hemin are sometimes beneficial.

Liver transplantation has been carried out in some EPP and

XLP patients with severe liver complications and is often successful

in the short term. However, the disease often recurs in the transplanted liver due to continued bone marrow production of excess

protoporphyrin. In a retrospective study of 17 liver-transplanted

EPP patients, 11 (65%) had recurrent EPP liver disease. Posttransplantation treatment with hematin and plasmapheresis should be

considered to prevent the recurrence of liver disease. However, bone

marrow transplantation, which has been successful in human EPP

and which prevented liver disease in a mouse model, should be considered after liver transplantation, if a suitable donor can be found.

Acknowledgment

The authors thank Dr. Karl E. Anderson for his review of the manuscript

and helpful comments and suggestions. This work is supported in part

by the Porphyrias Consortium (U54 DK083909), a part of the National

Institutes of Health (NIH) Rare Disease Clinical Research Network

(RDCRN), supported through collaboration between the NIH Office of

Rare Diseases Research (ORDR) at the National Center for Advancing

Translational Science (NCATS) and the National Institute of Diabetes

and Digestive and Kidney Diseases (NIDDK). The content is solely the

responsibility of the authors and does not necessarily represent the official

views of the National Institutes of Health.

■ FURTHER READING

Balwani M et al: Acute hepatic porphyrias: Recommendations for

evaluation and long-term management. Hepatology 66:1314, 2017.

Balwani M et al: Clinical, biochemical, and genetic characterization

of North American patients with erythropoietic protoporphyria and

X-linked protoporphyria. JAMA Dermatol 153:789, 2017.

Balwani M et al: Phase 3 trial of RNAi therapeutic givosiran for acute

intermittent porphyria. N Engl J Med 382:2289, 2020.

Bissell DM et al: Porphyria. N Engl J Med 377:862, 2017.

Chen B et al: Acute intermittent porphyria: Predicted pathogenicity of

HMBS variants indicates extremely low penetrance of the autosomal

dominant disease. Hum Mutat 37:1215, 2016.

Kazamel M et al: Porphyric neuropathy: Pathophysiology, diagnosis,

and updated management. Curr Neurol Neurosci Rep 20:56, 2020.

Langendonk JG et al: Afamelanotide for erythropoietic protoporphyria. N Engl J Med 373:48, 2015.

Singal AK et al: Hepatitis C treatment in patients with porphyria cutanea tarda. Am J Med Sci 353:523, 2017.

Tchernitchko D et al: A variant of peptide transporter 2 predicts the

severity of porphyria-associated kidney disease. J Am Soc Nephrol

28:1924, 2017.

Yasuda M et al: Liver transplantation for acute intermittent porphyria:

Biochemical and pathologic studies of the explanted liver. Mol Med

21:487, 2015.

3249 Disorders of Purine and Pyrimidine Metabolism CHAPTER 417

Basolateral membrane

to circulation

Uric acid

?

Uric acid

Glucose

Fructose

Na+

Dicarboxylates

OAT1

OAT3

SLC2A9v1

(GLUT9)

SLC13A3

Uric acid

Na+

Uric acid

Uric acid

Glucose

Fructose

Organic anions

monocarboxylates

Monocarboxylates

Dicarboxylates

Apical membrane

and tubule lumen

SLC2A9v2

(GLUT9∆N)

SLC5A8

SLC5A12

URAT1

OAT4

FIGURE 417-2 Schematic for handling of uric acid by the kidney. A complex interplay of transporters on both

the apical and basolateral aspects of the renal tubule epithelial cell is involved in the reabsorption of uric acid.

See text for details. Most uricosuric compounds inhibit URAT1 on the apical side, as well as OAT1, OAT3, and

GLUT9 on the basolateral side.

TABLE 417-1 Medications with Uricosuric Activity

Acetohexamide Glyceryl guaiacolate

Adrenocorticotropic hormone Glycopyrrolate

Ascorbic acid Halofenate

Azauridine Losartan

Benzbromarone Meclofenamate

Calcitonin Phenolsulfonphthalein

Chlorprothixene Phenylbutazone

Citrate Probenecid

Dicumarol Radiographic contrast agents

Diflunisal Salicylates (>2 g/d)

Estrogens Sulfinpyrazone

Fenofibrate Tetracycline that is outdated

Glucocorticoids Zoxazolamine

of urate is excreted by the kidneys, and most of the remainder is eliminated through the intestines.

The kidneys clear urate from the plasma and maintain physiologic

balance by utilizing specific organic anion transporters (OATs), including urate transporter 1 (URAT1, SLC22A12) (Fig. 417-2). In humans,

OAT1 (SLC22A6), OAT2 (SLC22A7), and OAT3 (SLC22A8) are

located on the basolateral membrane of renal proximal tubule cells.

OAT4 (SLC22A11), OAT10 (SLC22A13), and URAT1 are located on

the apical brush-border membrane of these cells. The latter transporters carry urate and other organic anions into the tubular cells

from the lumen in exchange for intracellular organic anions. Once

inside the cell, urate must pass to the basolateral side of the lumen

in a process controlled by voltage-dependent carriers, including

glucose transporter 9 (GLUT9, SLC2A9). Uricosuric compounds

(Table 417-1) directly inhibit URAT1 on the apical side of the tubular cell (so-called cis-inhibition). In contrast, antiuricosuric compounds

(those that promote hyperuricemia), such as nicotinate, pyrazinoate,

lactate, and other aromatic organic acids, serve as the exchange anion

inside the cell, thereby stimulating anion exchange

and urate reabsorption (trans-stimulation). The

activities of URAT1, other OATs, and sodium

anion transporters result in excretion of 8–12%

of the filtered urate as uric acid.

Most children have serum urate concentrations of 180–240 μmol/L (3–4 mg/dL). Levels

begin to rise in males during puberty but remain

low in females until menopause. The most recent

mean serum urate values for men and premenopausal women in the United States are 415 and

360 μmol/L (6.14 and 4.87 mg/dL), respectively,

according to National Health and Nutrition Evaluation Survey (NHANES) data for 2007–2008.

After menopause, values for women increase

to approximately those for men. In adulthood,

concentrations rise steadily over time and vary

with height, body weight, blood pressure, renal

function, and alcohol intake.

HYPERURICEMIA

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 (Chap. 372), urolithiasis, and

renal dysfunction (see below).

In general, hyperuricemia is defined as a

plasma (or serum) urate concentration >405

μmol/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. The prevalence of hyperuricemia is

increasing among ambulatory adults and even more markedly among

hospitalized patients. The prevalence of gout in the United States

more than doubled between the 1960s and the 1990s. Based on

NHANES data from 2007 to 2008, these trends continue, with an

approximate prevalence of gout among men of 5.9% (6.1 million)

and among women of 2.0% (2.2 million). Mean serum urate levels

rose to 6.14 mg/dL among men and 4.87 mg/dL among women, with

consequent hyperuricemia prevalences of 21.2 and 21.6%, respectively (with hyperuricemia defined as a serum urate level of >7.0 mg/dL

[415 μmol/L] for men and >5.7 mg/dL [340 μmol/L] for women).

These numbers represent a 1.2% increase in the prevalence of gout, a

0.15-mg/dL increase in the serum urate level, and a 3.2% increase in

the prevalence of hyperuricemia over figures reported in NHANES-III

(1988–1994). These rises are thought to be driven by increased obesity and hypertension and perhaps also by better medical care and

increased longevity.

■ CAUSES OF HYPERURICEMIA

Hyperuricemia may be classified as primary or secondary, depending on whether the cause is innate or 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 (Fig. 417-1,

Table 417-2).

Increased Urate Production Diet contributes to the serum urate

concentration in proportion to its purine content. Strict restriction

of purine intake reduces the mean serum urate level by ~60 μmol/L

(~1 mg/dL) and urinary uric acid excretion by ~1.2 mmol/d

(~200 mg/d). Foods high in nucleic acid content include liver, “sweetbreads” (i.e., thymus and pancreas), kidney, and anchovy.

Endogenous sources of purine production also influence the serum

urate level (Fig. 417-3). De novo purine biosynthesis is a multistep

process that forms inosine monophosphate (IMP). The rates of purine

biosynthesis and urate production are predominantly determined

3250 PART 12 Endocrinology and Metabolism

by amidophosphoribosyltransferase (amidoPRT), which combines

phosphoribosylpyrophosphate (PRPP) and glutamine. A secondary

regulatory pathway is the salvage of purine bases by hypoxanthine

phosphoribosyltransferase (HPRT). HPRT catalyzes the combination

of the purine bases hypoxanthine and guanine with PRPP to form

the respective ribonucleotides IMP and guanosine monophosphate

(GMP).

Serum urate levels are closely coupled to the rates of de novo purine

biosynthesis, which is driven in part by the level of PRPP, as evidenced

by two X-linked inborn errors of purine metabolism (Table 417-3).

Both increased PRPP synthetase activity and HPRT deficiency are

associated with overproduction of purines, hyperuricemia, and hyperuricaciduria (see below for clinical descriptions).

Accelerated purine nucleotide degradation can also cause

hyperuricemia—i.e., with conditions of rapid cell turnover, proliferation, or cell death, as in leukemic blast crises, cytotoxic therapy for

malignancy, hemolysis, or rhabdomyolysis. Hyperuricemia can result

from excessive degradation of skeletal muscle ATP after strenuous

physical exercise or status epilepticus and in glycogen storage disease

types III, V, and VII (Chap. 419). The hyperuricemia of myocardial

infarction, smoke inhalation, and acute respiratory failure may also be

related to accelerated breakdown of ATP.

Decreased Uric Acid Excretion More than 90% of individuals

with sustained hyperuricemia have a defect in the renal handling of

uric acid. For any given plasma urate concentration, patients who have

gout excrete ~40% less uric acid than those who do not. When plasma

urate levels are raised by purine ingestion or infusion, uric acid excretion increases in patients with and without gout; however, in those with

gout, plasma urate concentrations must be 60–120 μmol/L (1–2 mg/

dL) higher than normal to achieve equivalent uric acid excretion rates.

Diminished uric acid excretion could theoretically result from

decreased glomerular filtration, decreased tubular secretion, or

enhanced tubular reabsorption. Decreased urate filtration does not

appear to cause primary hyperuricemia but does contribute to the

hyperuricemia of renal insufficiency. Although hyperuricemia is

invariably present in chronic renal disease, the correlation among

serum creatinine, urea nitrogen, and urate concentrations is poor.

Extrarenal clearance of uric acid increases as renal damage becomes

more severe.

Many agents that cause hyperuricemia exert their effects by stimulating reabsorption rather than inhibiting secretion. This stimulation appears to occur through a process of “priming” renal urate

reabsorption through the sodium-dependent loading of proximal

tubular epithelial cells with anions capable of trans-stimulating urate

reabsorption. The sodium-coupled monocarboxyl transporters

SMCT1 and 2 (SLC5A8, SLC5A12) in the brush border of the proximal tubular cells mediate sodium-dependent loading of these cells

with monocarboxylates. A similar transporter, SLC13A3, mediates

sodium-dependent influx of dicarboxylates into the epithelial cell from

the basolateral membrane. Some of these carboxylates are well known

to cause hyperuricemia, including pyrazinoate (from pyrazinamide

treatment), nicotinate (from niacin therapy), and the organic acids

lactate, β-hydroxybutyrate, and acetoacetate. The mono- and divalent

anions then become substrates for URAT1 and OAT4, respectively, and

are exchanged for uric acid from the proximal tubule. Increased blood

levels of these anions result in their increased glomerular filtration and

greater reabsorption by proximal tubular cells. The increased intraepithelial cell concentrations lead to increased uric acid reabsorption by

promoting URAT1-, OAT4-, and OAT10-dependent anion exchange.

Low doses of salicylates also promote hyperuricemia by this mechanism. Sodium loading of proximal tubular cells also provokes urate

retention by reducing extracellular fluid volume and increasing angiotensin II, insulin, and parathyroid hormone release. Additional OAT1,

OAT2, and OAT3 are involved in the movement of uric acid through

the basolateral membrane, although the detailed mechanisms are still

being elucidated.

GLUT9 (SLC2A9) is an electrogenic hexose transporter with splicing variants that mediate co-reabsorption of uric acid along with glucose and fructose at the apical membrane (GLUT9ΔN/SLC2A9v2) as

well as through the basolateral membrane (SLC2A9v1) and thus into

the circulation. GLUT9 has recently been identified as a high-capacity

urate transporter, with rates 45–60 times faster than its glucose/

fructose transport activity. GLUT9 may be responsible for the observed

PRA

SAICAR

Guanosine

Xanthine

Urate

IMP

PRPP

AICAR

Adenine

Inosine

2,8 Dihydroxyadenine

NH3

Purine

nucleotide

cycle

De novo biosynthesis

PRPP Glutamine

Ribose-5-P

ATP

Feedback

inhibition

Feedback

inhibition

1 2

3

3

4

6

5 5

7 7

8

9

5

10 10

10

GMP AMP

Adenosine

Guanine Hypoxanthine

PRPP

FIGURE 417-3 Abbreviated scheme of purine metabolism. (1) Phosphoribosyl

pyrophosphate (PRPP) synthetase, (2) amidophosphoribosyltransferase (amidoPRT),

(3) adenylosuccinate lyase, (4) (myo-)adenylate (AMP) deaminase, (5) 5′-nucleotidase,

(6) adenosine deaminase, (7) purine nucleoside phosphorylase, (8) hypoxanthine

phosphoribosyltransferase (HPRT), (9) adenine phosphoribosyltransferase (APRT),

and (10) xanthine oxidase. AICAR, aminoimidazole carboxamide ribotide; ATP,

adenosine triphosphate; GMP, guanylate; IMP, inosine monophosphate; PRA,

phosphoribosylamine; SAICAR, succinylaminoimidazole carboxamide ribotide.

TABLE 417-2 Classification of Hyperuricemia by Pathophysiology

Urate Overproduction

Primary idiopathic

HPRT deficiency

PRPP synthetase

overactivity

Hemolytic processes

Lymphoproliferative

diseases

Myeloproliferative

diseases

Polycythemia vera

Psoriasis

Paget’s disease

Glycogenosis III, V, and

VII

Rhabdomyolysis

Exercise

Alcohol

Obesity

Purine-rich diet

Decreased Uric Acid Excretion

Primary idiopathic

Renal insufficiency

Polycystic kidney disease

Diabetes insipidus

Hypertension

Acidosis

Lactic acidosis

Diabetic ketoacidosis

Starvation ketosis

Berylliosis

Sarcoidosis

Lead intoxication

Hyperparathyroidism

Hypothyroidism

Toxemia of pregnancy

Bartter’s syndrome

Down’s syndrome

Drug ingestion

Salicylates (<2 g/d)

Diuretics

Alcohol

Levodopa

Ethambutol

Pyrazinamide

Nicotinic acid

Cyclosporine

Combined Mechanism

Glucose-6-phosphatase

deficiency

Fructose-1-phosphate

aldolase deficiency

Alcohol

Shock

Abbreviations: HPRT, hypoxanthine phosphoribosyltransferase; PRPP,

phosphoribosylpyrophosphate.

3251 Disorders of Purine and Pyrimidine Metabolism CHAPTER 417

TABLE 417-3 Inborn Errors of Purine Metabolism

ENZYME ACTIVITY INHERITANCE CLINICAL FEATURES LABORATORY FEATURES

Hypoxanthine

phosphoribosyltransferase

Complete deficiency X-linked Self-mutilation, choreoathetosis, gout,

and uric acid lithiasis

Hyperuricemia, hyperuricosuria

Partial deficiency X-linked Gout and uric acid lithiasis Hyperuricemia, hyperuricosuria

Phosphoribosylpyrophosphate

synthetase

Overactivity X-linked Gout, uric acid lithiasis, and deafness Hyperuricemia, hyperuricosuria

Adenine phosphoribosyltransferase Deficiency Autosomal recessive 2,8-Dihydroxyadenine lithiasis —

Xanthine oxidase Deficiency Autosomal recessive Xanthinuria and xanthine lithiasis Hypouricemia, hypouricosuria

Adenylosuccinate lyase Deficiency Autosomal recessive Autism and psychomotor retardation —

Myoadenylate deaminase Deficiency Autosomal recessive Myopathy with exercise intolerance

or asymptomatic

—

Adenosine deaminase Deficiency Autosomal recessive Severe combined immunodeficiency

disease and chondro-osseous

dysplasia

—

Purine nucleoside phosphorylase Deficiency Autosomal recessive T cell–mediated immunodeficiency —

association of the consumption of fructose-sweetened soft drinks with

an increased risk of hyperuricemia and gout. Genome-wide association

studies (GWAS) suggest that polymorphisms in SLC2A9 may play an

important role in susceptibility to gout in the Caucasian population.

The presence of one predisposing variant allele increases the relative

risk of developing gout by 30–70%, most likely by increasing expression of the shorter isoform, SLC2A9v2 (GLUT9ΔN). GWAS have identified over 30 loci associated with serum urate levels, most encoding

transporters in the gut or kidney. Recent meta-analyses suggest that

genetic polymorphisms may explain up to 23.9% of the variation in

serum urate levels, much higher than previously appreciated. However,

the utility of genetic testing for relevant polymorphisms remains investigational with few exceptions. The Q141K variant of ABCG2, which

encodes a urate transporter that secretes urate in the small intestine,

is associated with early onset and severe gout and resistance to allopurinol. The HLA-B*50:10 genotype is associated with allopurinol hypersensitivity in Asian populations. This field is evolving rapidly.

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 may also be a factor. Consumption of beer confers a greater

risk of gout than liquor, and moderate wine intake does not increase

gout risk. Intake of red meat and fructose increases the risk of gout,

whereas intake of low-fat dairy products, purine-rich vegetables, whole

grains, nuts and legumes, less sugary fruits, coffee, and vitamin C

reduces the risk.

EVALUATION

Hyperuricemia does not necessarily represent a disease, nor is it a specific indication for therapy. The decision to treat depends on the cause

and the potential consequences of hyperuricemia in each individual.

Quantification of uric acid excretion can be used to determine

whether hyperuricemia is caused by overproduction or decreased

excretion. On a purine-free diet, men with normal renal function

excrete <3.6 mmol/d (600 mg/d). Thus, the hyperuricemia of individuals who excrete uric acid above this level while on a purine-free diet is

due to purine overproduction; for those who excrete lower amounts on

the purine-free diet, it is due to decreased excretion. If the assessment is

performed while the patient is on a regular diet, the level of 4.2 mmol/d

(800 mg/d) can be used as the discriminating value.

COMPLICATIONS

The most recognized complication of hyperuricemia is gouty arthritis.

NHANES 2007–2008 found a prevalence of gout among U.S. adults of

3.9%, with figures of ~6% for men and ~2% for women. The higher

the serum urate level, the more likely an individual is to develop gout.

In one study, the incidence of gout was 4.9% among individuals with

serum urate concentrations >540 μmol/L (>9.0 mg/dL) as opposed

to only 0.5% among those with values between 415 and 535 μmol/L

(7.0 and 8.9 mg/dL). The complications of gout correlate with both the

duration and the severity of hyperuricemia. For further discussion of

gout, see Chap. 372.

Hyperuricemia also causes several renal problems: (1) nephrolithiasis; (2) urate nephropathy, a rare cause of renal insufficiency attributed

to monosodium urate crystal deposition in the renal interstitium;

and (3) uric acid nephropathy, a reversible cause of acute renal failure

resulting from deposition of large amounts of uric acid crystals in the

renal collecting ducts, pelvis, and ureters.

Nephrolithiasis Uric acid nephrolithiasis occurs most commonly,

but not exclusively, in individuals with gout. In gout, the prevalence of

nephrolithiasis correlates with the serum and urinary uric acid levels,

reaching ~50% with serum urate levels of 770 μmol/L (13 mg/dL) or

urinary uric acid excretion >6.5 mmol/d (1100 mg/d).

Uric acid stones can develop in individuals with no evidence of

arthritis, only 20% of whom are hyperuricemic. Uric acid can also play

a role in other types of kidney stones. Some individuals who do not

have gout but have calcium oxalate or calcium phosphate stones have

hyperuricemia or hyperuricaciduria. Uric acid may act as a nidus on

which calcium oxalate can precipitate or lower the formation product

for calcium oxalate crystallization.

Urate Nephropathy Urate nephropathy, sometimes referred to

as urate nephrosis, is a late manifestation of severe gout and is characterized histologically by deposits of monosodium urate crystals

surrounded by a giant-cell inflammatory reaction in the medullary

interstitium and pyramids. The disorder is now rare and cannot be

diagnosed in the absence of gouty arthritis. The lesions may be clinically silent or cause proteinuria, hypertension, and renal insufficiency.

Uric Acid Nephropathy This reversible cause of acute renal failure is due to precipitation of uric acid in renal tubules and collecting

ducts that obstructs urine flow. Uric acid nephropathy develops following sudden urate overproduction and marked hyperuricaciduria.

Factors that favor uric acid crystal formation include dehydration and

acidosis. This form of acute renal failure occurs most often during

an aggressive “blastic” phase of leukemia or lymphoma prior to or

coincident with cytolytic therapy but has also been observed in individuals with other neoplasms, following epileptic seizures, and after

vigorous exercise with heat stress. Autopsy studies have demonstrated

intraluminal precipitates of uric acid, dilated proximal tubules, and

normal glomeruli. The initial pathogenic events are believed to include

obstruction of collecting ducts with uric acid and obstruction of the

distal renal vasculature.

If recognized, uric acid nephropathy is potentially reversible.

Appropriate therapy has reduced the mortality rate from ~50% to near

zero. Serum levels cannot be relied on for diagnosis because this condition has developed in the presence of urate concentrations varying

from 720–4800 μmol/L (12–80 mg/dL). The distinctive feature is the

3252 PART 12 Endocrinology and Metabolism

urinary uric acid concentration. In most forms of acute renal failure

with decreased urine output, urinary uric acid content is either normal

or reduced, and the ratio of uric acid to creatinine is <1. In acute uric

acid nephropathy, the ratio of uric acid to creatinine in a random urine

sample or a 24-h specimen is >1, and a value that high is essentially

diagnostic.

HYPERURICEMIA AND METABOLIC

SYNDROME

Metabolic syndrome (Chap. 408) is characterized by abdominal obesity with visceral adiposity, impaired glucose tolerance due to insulin

resistance with hyperinsulinemia, hypertriglyceridemia, increased

low-density lipoprotein cholesterol, decreased high-density lipoprotein

cholesterol, and hyperuricemia. Hyperinsulinemia reduces the renal

excretion of uric acid and sodium. Not surprisingly, hyperuricemia

resulting from euglycemic hyperinsulinemia may precede the onset

of type 2 diabetes, hypertension, coronary artery disease, and gout in

individuals with metabolic syndrome.

TREATMENT

Hyperuricemia

ASYMPTOMATIC HYPERURICEMIA

Hyperuricemia is present in ~21% of the population and in at least

25% of hospitalized individuals. The vast majority of hyperuricemic persons are at no clinical risk. In the past, the association of

hyperuricemia with cardiovascular disease and renal failure led to

the use of urate-lowering agents for patients with asymptomatic

hyperuricemia. This practice is no longer recommended except for

individuals receiving cytolytic therapy for neoplastic disease, who

are treated with urate-lowering agents in an effort to prevent uric

acid nephropathy. Because hyperuricemia can be a component of

the metabolic syndrome, its presence is an indication to screen for

and aggressively treat any accompanying obesity, hyperlipidemia,

diabetes mellitus, or hypertension.

Hyperuricemic individuals, especially those with higher serum

urate levels, are at risk for the development of gouty arthritis. However, most hyperuricemic persons never develop gout, and prophylactic treatment is not indicated. Furthermore, neither structural

kidney damage nor tophi are identifiable before the first attack.

Reduced renal function cannot be attributed to asymptomatic

hyperuricemia and available evidence does not yet support treatment of asymptomatic hyperuricemia to alter progression of renal

dysfunction in patients with renal disease. An increased risk of

stone formation in those with asymptomatic hyperuricemia has not

been established.

Thus, because treatment with specific antihyperuricemic agents

entails inconvenience, cost, and potential toxicity, routine treatment of asymptomatic hyperuricemia cannot be justified other

than for prevention of acute uric acid nephropathy. In addition,

routine screening for asymptomatic hyperuricemia is not recommended. If hyperuricemia is diagnosed, however, the cause should

be determined. Causal factors should be corrected if the condition

is secondary, and associated problems such as hypertension, hypercholesterolemia, diabetes mellitus, and obesity should be treated.

SYMPTOMATIC HYPERURICEMIA

See Chap. 372 for treatment of gout, including urate nephrosis.

Nephrolithiasis Antihyperuricemic therapy is recommended for

the individual who has both gouty arthritis and either uric acid– or

calcium-containing stones, both of which may occur in association

with hyperuricaciduria. Regardless of the nature of the calculi,

fluid ingestion should be sufficient to produce a daily urine volume

>2 L. Alkalinization of the urine with sodium bicarbonate or acetazolamide may be justified to increase the solubility of uric acid.

Specific treatment of uric acid calculi requires reducing the urine

uric acid concentration with a xanthine oxidase inhibitor, such as

allopurinol or febuxostat. These agents decrease the serum urate

concentration and the urinary excretion of uric acid in the first

24 h, with a maximal reduction within 2 weeks. Allopurinol can

be given once a day because of the long half-life (18 h) of its active

metabolite, oxypurinol. In the febuxostat trials, the generally recommended dose of allopurinol (300 mg/d) was effective at achieving a target serum urate concentration <6.0 mg/dL (357 μmol/L) in

<50% of patients; this result suggested that higher doses should be

considered. Allopurinol is effective in patients with renal insufficiency, but the dose should be reduced. Allopurinol is also useful in

reducing the recurrence of calcium oxalate stones in patients with

gout and in individuals with hyperuricemia or hyperuricaciduria

who do not have gout. Febuxostat (40–80 mg/d) is also taken once

daily, and doses do not need to be adjusted in the presence of mild

to moderate renal dysfunction. Potassium citrate (30–80 mmol/d

orally in divided doses) is an alternative therapy for patients

with uric acid stones alone or mixed calcium/uric acid stones. A

xanthine oxidase inhibitor is also indicated for the treatment of

2,8-dihydroxyadenine kidney stones.

Uric Acid Nephropathy Uric acid nephropathy is often preventable, and immediate appropriate therapy has greatly reduced

the mortality rate. Vigorous IV hydration and diuresis with furosemide dilute the uric acid in the tubules and promote urine flow

to ≥100 mL/h. The administration of acetazolamide (240–500 mg

every 6–8 h) and sodium bicarbonate (89 mmol/L) IV enhances

urine alkalinity and thereby solubilizes more uric acid. It is important to ensure that the urine pH remains >7.0 and to watch for circulatory overload. In addition, antihyperuricemic therapy in the form

of allopurinol in a single dose of 8 mg/kg is administered to reduce

the amount of urate that reaches the kidney. If renal insufficiency

persists, subsequent daily doses should be reduced to 100–200 mg

because oxypurinol, the active metabolite of allopurinol, accumulates in renal failure. Despite these measures, hemodialysis may be

required. Urate oxidase (rasburicase) can also be administered IV

to prevent or to treat tumor lysis syndrome.

■ HYPOURICEMIA

Hypouricemia, defined as a serum urate concentration <120 μmol/L

(<2.0 mg/dL), can result from decreased production of urate, increased

excretion of uric acid, or a combination of both mechanisms. This

condition occurs in <0.2% of the general population and <0.8% of hospitalized individuals. Hypouricemia causes no symptoms or pathology

and therefore requires no therapy.

Most hypouricemia results from increased renal uric acid excretion.

The finding of normal amounts of uric acid in a 24-h urine collection

from an individual with hypouricemia is evidence for a renal cause.

Medications with uricosuric properties (Table 417-1) include aspirin

(at doses >2.0 g/d), losartan, fenofibrate, x-ray contrast materials,

and glyceryl guaiacolate. Total parenteral hyperalimentation can also

cause hypouricemia, possibly a result of the high glycine content of the

infusion formula. Other causes of increased urate clearance include

conditions such as neoplastic disease, hepatic cirrhosis, diabetes mellitus, and inappropriate secretion of vasopressin; defects in renal tubular

transport such as primary Fanconi syndrome and Fanconi syndromes

caused by Wilson’s disease, cystinosis, multiple myeloma, and heavy

metal toxicity; and isolated congenital defects in the bidirectional

transport of uric acid. Hypouricemia can be a familial disorder that

is generally inherited in an autosomal recessive manner. Most cases

are caused by a loss of function mutation in SLC22A12, the gene that

encodes URAT-1, resulting in increased renal urate clearance. Individuals with normal SLC22A12 most likely have a defect in other urate transporters. Although hypouricemia is usually asymptomatic, some patients

suffer from urate nephrolithiasis or exercise-induced renal failure.

■ SELECTED INBORN ERRORS OF PURINE AND

PYRIMIDINE METABOLISM

(See also Table 417-3, Table 417-4, Fig. 417-3, and Fig. 417-4). More

than 30 defects in human purine and pyrimidine metabolic pathways

have been identified thus far. Many are benign, but about half are