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InternalMed_Harrison. individual PCT patient. Patients with PCT characteristically have chronic liver disease and sometimes cirrhosis and are at risk for hepatocellular carcinoma. Various chemicals can also induce PCT; an epidemic of PCT occurred in eastern Turkey in the 1950s as a consequence of wheat contaminated with the fungicide hexachlorobenzene. PCT also occurs after exposure to other chemicals, including diand trichlorophenols and 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD, dioxin).


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InternalMed_Harrison. FIGURE 430-3 Typical cutaneous lesions in a patient with porphyria cutanea tarda. Chronic, crusted lesions resulting from blistering due to photosensitivity on the dorsum of the hand of a patient with porphyria cutanea tarda. (Courtesy of Dr. Karl E. Anderson; with permission.) Diagnosis Porphyrins are increased in the liver, plasma, urine, and stool. The urinary ALA level may be slightly increased, but the PBG level is normal. Urinary porphyrins consist mostly of uroporphyins and heptacarboxylate porphyrin, with lesser amounts of coproporphyrin and hexaand pentacarboxylate porphyrins. Plasma porphyrins are also increased, and fluorometric scanning of diluted plasma at neutral pH can rapidly distinguish VP and PCT (Table 430-3). Isocoproporphyrins, which are increased in feces and sometimes in plasma and urine, are diagnostic for hepatic URO decarboxylase deficiency.


InternalMed_Harrison

InternalMed_Harrison. Type 2 PCT and HEP can be distinguished from type 1 by finding decreased URO decarboxylase in erythrocytes. URO decarboxylase activity in liver, erythrocytes, and cultured skin fibroblasts in type 2 PCT is approximately 50% of normal in affected individuals and in family members with latent disease. In HEP, the URO decarboxylase activity is markedly deficient, with typical levels of 3–10% of normal. Over 121 mutations have been identified in the UROD gene (Human Gene Mutation Database; www.hgmd.org). Of the mutations listed in the database, ~65% are missense or nonsense and ~10% are splice-site mutations. Most UROD mutations have been identified in only one or two families.


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InternalMed_Harrison. Alcohol, estrogens, iron supplements, and, if possible, any drugs that may exacerbate the disease should be discontinued, but this step does not always lead to improvement. A complete response can almost always be achieved by the standard therapy, repeated phlebotomy, to reduce hepatic iron. A unit (450 mL) of blood can be removed every 1–2 weeks. The aim is to gradually reduce excess hepatic iron until the serum ferritin level reaches the lower limits of normal. Because iron overload is not marked in most cases, remission may occur after only five or six phlebotomies; however, PCT patients with hemochromatosis may require more treatments to bring their iron levels down to the normal range. To document improvement in PCT, it is most convenient to follow the total plasma porphyrin concentration, which becomes normal some time after the target ferritin level is reached. Hemoglobin levels or hematocrits and serum ferritin should be followed closely to prevent development of iron


InternalMed_Harrison

InternalMed_Harrison. concentration, which becomes normal some time after the target ferritin level is reached. Hemoglobin levels or hematocrits and serum ferritin should be followed closely to prevent development of iron deficiency and anemia. After remission, continued phlebotomy may not be needed. Plasma porphyrin levels are followed at 6to 12-month intervals for early detection of recurrences, which are treated by additional phlebotomy.


InternalMed_Harrison

InternalMed_Harrison. An alternative when phlebotomy is contraindicated or poorly tolerated is a low-dose regimen of chloroquine or hydroxychloroquine, both of which complex with the excess porphyrins and promote their excretion. Small doses (e.g., 125 mg chloroquine phosphate twice weekly) should be given, because standard doses can induce transient, sometimes marked increases in photosensitivity and hepatocellular damage. Recent studies indicate that low-dose hydroxychloroquine is as safe and effective as phlebotomy in PCT. Hepatic imaging can diagnose or exclude complicating hepatocellular carcinoma. Treatment of PCT in patients with end-stage renal disease is facilitated by administration of erythropoietin.


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InternalMed_Harrison. HCP is an autosomal dominant hepatic porphyria that results from the half-normal activity of COPRO oxidase. The disease presents with acute attacks, as in AIP. Cutaneous photosensitivity also may occur, but much less commonly than in VP. HCP patients may have acute attacks and cutaneous photosensitivity together or separately. HCP is less common than AIP and VP. Homozygous dominant HCP and harderoporphyria, a biochemically distinguishable variant of HCP, present with clinical symptoms in children (see below). Clinical Features HCP is influenced by the same factors that cause attacks in AIP. The disease is latent before puberty, and symptoms, which are virtually identical to those of AIP, are more common in women. HCP is generally less severe than AIP. Blistering skin lesions are identical to PCT and VP and begin in childhood in rare homozygous cases.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis COPRO III is markedly increased in the urine and feces in symptomatic patients, and often persists, especially in feces, when there are no symptoms. Urinary ALA and PBG levels are increased (but less than in AIP) during acute attacks, but may revert to normal more quickly than in AIP when symptoms resolve. Plasma porphyrins are usually normal or only slightly increased, but they may be higher in cases with skin lesions. The diagnosis of HCP is readily confirmed by increased fecal porphyrins consisting almost entirely of COPRO III, which distinguishes it from other porphyrias.


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InternalMed_Harrison. Although the diagnosis can be confirmed by measuring COPRO oxidase activity, the assays for this mitochondrial enzyme are not widely available and require cells other than erythrocytes. To date, over 64 mutations have been identified in the CPOX gene, 67% of which are missense or nonsense (Human Gene Mutation Database; www.hgmd .org). Detection of a CPOX mutation in a symptomatic individual permits the identification of asymptomatic family members. Neurologic symptoms are treated as in AIP (see above). Phlebotomy and chloroquine are not effective for the cutaneous lesions.


InternalMed_Harrison

InternalMed_Harrison. Neurologic symptoms are treated as in AIP (see above). Phlebotomy and chloroquine are not effective for the cutaneous lesions. 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 Holland 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.


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InternalMed_Harrison. Clinical Features VP can present with skin photosensitivity, acute neurovisceral crises, or both. In two large studies of VP patients, 59% had only skin lesions, 20% had only acute attacks, and 22% 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 2531 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.


InternalMed_Harrison

InternalMed_Harrison. 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 174 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 two families.


InternalMed_Harrison

InternalMed_Harrison. Acute attacks are treated as in AIP, and hemin should be started early in most cases. Other than avoiding sun exposure, there are few effective measures for treating the skin lesions. β-Carotene, phlebotomy, and chloroquine are not helpful. In the erythropoietic porphyrias, excess porphyrins from bone marrow erythrocyte precursors are transported via the plasma to the skin and lead to cutaneous photosensitivity. 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.


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InternalMed_Harrison. 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, late-onset disease have been reported recently.


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InternalMed_Harrison. 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 mutations in the erythroid ALAS2 gene. 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 The Porphyrias 2532 several responsive patients. Cofactor supplementation may make it possible to eliminate or reduce the frequency of transfusion. Unresponsive patients may be transfusion-dependent and require chelation therapy.


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Clinical Features Severe cutaneous photosensitivity typically begins in early infancy. The skin over light-exposed areas is friable, and bullae and vesicles are prone to rupture and infection. Skin thickening, focal hypoand 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 probably 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.


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InternalMed_Harrison. 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 over 48 mutations in the UROS gene, including four 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, mutation of which typically causes XLP. One mutation (p.ArgR216WTrp) in GATA1,


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InternalMed_Harrison. of the disease. The CEP phenotype may be modulated by sequence variations in the erythroid specific ALA synthase 2, 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.


InternalMed_Harrison

InternalMed_Harrison. Severe cases often require transfusions for anemia. Chronic transfusions of sufficient blood 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. β-Carotene may be of some value. Complicating bacterial infections should be treated promptly. Recently, bone marrow and cord blood transplantation has proven curative in several transfusion-dependent children, providing the rationale for stem cell gene therapy.


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InternalMed_Harrison. EPP is an inherited disorder resulting from the deficient activity of ferrochelatase (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 accumulates in bone marrow reticulocytes and then appears in plasma, is taken up in the liver, and is excreted in bile and feces. Protoporphyrin transported to the vessels in the skin causes the nonblistering photosensitivity. In most symptomatic patients (~90%) with this autosomal recessive disorder, a mutation in one FECH allele is inherited with a relatively common (~10% of normal whites) intronic 3 (IVS3) alteration (IVS3– 48T>C) that results in the low expression of the normal enzyme. In about 10% of EPP families, two FECH mutations have been found. Recently, deletion mutations in exon 11 of the ALAS2 gene


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InternalMed_Harrison. (IVS3– 48T>C) that results in the low expression of the normal enzyme. In about 10% of EPP families, two FECH mutations have been found. Recently, deletion mutations in exon 11 of the ALAS2 gene have been described, causing XLP that is clinically indistinguishable from EPP. The deletion of the C-terminal amino acids of ALAS2 results in its increased activity and the accumulation of protoporphyrin. XLP accounts for approximately 2–10% of cases with the EPP phenotype in Europe and North America.


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InternalMed_Harrison. Clinical Features Skin photosensitivity, which differs from that in other porphyrias, usually begins in childhood and consists of pain, redness, and itching occurring within minutes of sunlight exposure (Fig. 430-4). Photosensitivity is associated with substantial elevations in erythrocyte protoporphyrin and occurs only in patients with genotypes that result in ferrochelatase activities below ~35% of normal. Vesicular lesions are uncommon. Redness, swelling, burning, and itching can develop shortly after sun exposure and resemble angioedema. Pain symptoms may seem out of proportion to the visible skin involvement. Sparse vesicles and bullae occur in ~10% of cases. 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 levels and symptoms of photosensitivity remain remarkably stable over many


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InternalMed_Harrison. is rare, as are pigment changes, friability, and hirsutism. Unless hepatic or other complications develop, protoporphyrin levels and symptoms of photosensitivity remain remarkably stable over many years in most patients. Factors that exacerbate the hepatic porphyrias play little or no role in EPP.


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InternalMed_Harrison. The primary source of excess protoporphyrin is the bone marrow reticulocytes. Erythrocyte protoporphyrin is free (not complexed with zinc) and is mostly bound to hemoglobin. In plasma, protoporphyrin is bound to albumin. Hemolysis and anemia are usually absent or mild.


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InternalMed_Harrison. Although EPP is an erythropoietic porphyria, up to 20% of EPP patients may have minor abnormalities of liver function, and in about 5% of these patients the accumulation of protoporphyrins causes chronic liver disease that can progress to liver failure and death. Protoporphyrin is insoluble, and excess amounts form crystalline structures in liver cells (Fig. 430-4) 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 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


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InternalMed_Harrison. FIGURE 430-4 Erythema and edema of the hands due to acute photosensitivity in a 10-year-old boy with erythropoietic protoporphyria. (From P Poblette-Gutierrez et al: Eur J Dermatol 16:230, 2006.) composed at least in part of protoporphyrin occur in some patients. Hepatic complications appear to be higher in autosomal recessive EPP due to two FECH mutations and in XLP.


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InternalMed_Harrison. diagnosis A substantial increase in erythrocyte protoporphyrin, which is predominantly free and not complexed with zinc, is the hallmark of EPP. Protoporphyrin levels are also variably increased in bone marrow, plasma, bile, and feces. Erythrocyte protoporphyrin 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 is complexed with zinc. Therefore, after an increase in erythrocyte protoporphyrin 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 a fluorescence microscopy at 620 nm. Urinary levels of porphyrins and porphyrin precursors are normal. Ferrochelatase activity in cultured lymphocytes or fibroblasts is


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InternalMed_Harrison. exhibit red fluorescence under a fluorescence microscopy at 620 nm. Urinary levels of porphyrins and porphyrin precursors are normal. Ferrochelatase activity in cultured lymphocytes or fibroblasts is decreased. 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, over 190 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). Studies suggest that EPP patients with a null allele (and the IVS3–48T>C low expression allele) have a greater risk for developing severe liver complications.


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InternalMed_Harrison. In XLP, the erythrocyte protoporphyrin levels appear to be higher than other forms of EPP and the proportions of free and zinc protopophyrins may reach 50%. To date, four ALAS2 mutations, three deletions of one to four bases, and one novel nonsense mutation have been described, which markedly increase ALA synthase 2 activity and cause XLP. XLP accounts for about 2% of patients with the EPP phenotype in Western Europe. Recent studies show that about 10% of North American patients with the EPP phenotype have XLP.


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InternalMed_Harrison. Avoiding sunlight exposure and wearing clothing designed to provide protection for conditions with chronic photosensitivity are essential. Oral β-carotene (120–180 mg/dL) may improve tolerance to sunlight in some patients. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. The dosage may need to be adjusted to maintain serum carotene levels in the recommended range of 10–15 mmol/L (600–800 mg/dL). Mild skin discoloration due to carotenemia is the only significant side effect. Afamelanotide, an α-melanocyte-stimulating hormone (MSH) analogue has completed phase III clinical trials in the United States for patients with EPP and XLP.


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InternalMed_Harrison. 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. Splenectomy may be helpful when the disease is accompanied by hemolysis and significant splenomegaly. Plasmapheresis and intravenous hemin are sometimes beneficial.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. MB is supported by a career development award K23-DK-095946 The Porphyrias


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InternalMed_Harrison. The Porphyrias Disorders of Purine and Pyrimidine Metabolism Christopher M. Burns, Robert L. Wortmann Purines (adenine and guanine) and pyrimidines (cytosine, thymine, uracil) serve fundamental roles in the replication of genetic mate-431e rial, 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.


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InternalMed_Harrison. Uric acid is the final breakdown product of purine degradation in humans. It is a weak diprotic acid with pK a 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.


InternalMed_Harrison

InternalMed_Harrison. 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, 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. 431e-1). Normally, two-thirds to three-fourths of


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InternalMed_Harrison. FIgURE 431e-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. urate is excreted by the kidneys, and most of the remainder is eliminated 431e-1 through the intestines.


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InternalMed_Harrison. 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. 431e-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 431e-1) directly inhibit URAT1 on the apical side of the tubular cell (so-called cisinhibition). In contrast, antiuricosuric compounds (those that promote hyperuricemia), such as nicotinate, pyrazinoate,


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InternalMed_Harrison. directly inhibit URAT1 on the apical side of the tubular cell (so-called cisinhibition). 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.


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InternalMed_Harrison. 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 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. 395), urolithiasis, and renal dysfunction (see below).


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InternalMed_Harrison. 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 2007–2008, 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


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


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InternalMed_Harrison. 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. 431e-1, Table 431e-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 CHAPTER 431e Disorders of Purine and Pyrimidine Metabolism FIgURE 431e-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.


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InternalMed_Harrison. (~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. 431e-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 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).


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InternalMed_Harrison. 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 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 431e-3). Both increased PRPP synthetase activity and HPRT deficiency are associated with overproduction of purines, hyperuricemia, and hyperuricaciduria (see below for clinical descriptions).


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InternalMed_Harrison. 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. 433e). The hyperuricemia of myocardial infarction, smoke inhalation, and acute respiratory failure may also be related to accelerated breakdown of ATP.


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InternalMed_Harrison. 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. Uric acid ? retically 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 Glycogenosis III, V, and VII Purine-rich diet Lymphoproliferative diseases


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InternalMed_Harrison. Glycogenosis III, V, and VII Purine-rich diet Lymphoproliferative diseases Lactic acidosis Diabetic ketoacidosis Starvation ketosis Drug ingestion Berylliosis Salicylates (<2 g/d) Sarcoidosis Diuretics Lead intoxication Alcohol Hyperparathyroidism Levodopa Hypothyroidism Ethambutol Toxemia of pregnancy Pyrazinamide Bartter’s syndrome Nicotinic acid Down syndrome Cyclosporine Abbreviations: HPRT, hypoxanthine phosphoribosyltransferase; PRPP, phosphoribosylpyrophosphate. 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 55 77 8 9 5 1010 10 GMP AMP Adenosine HypoxanthineGuanine PRPP FIgURE 431e-3 Abbreviated scheme of purine metabolism.


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InternalMed_Harrison. FIgURE 431e-3 Abbreviated scheme of purine metabolism. (1) Phosphoribosylpyrophosphate (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. PRA, phosphoribosylamine; SAICAR, succinylaminoimidazole carboxamide ribotide; AICAR, aminoimidazole carboxamide ribotide; GMP, guanylate; IMP, inosine mono-phosphate; ATP, adenosine triphosphate. serum creatinine, urea nitrogen, and urate concentrations is poor. Extrarenal clearance of uric acid increases as renal damage becomes more severe.


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InternalMed_Harrison. 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 431e-3 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 monoand divalent anions then become substrates for URAT1 and OAT4, respectively, and are


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InternalMed_Harrison. nicotinate (from niacin therapy), and the organic acids lactate, β-hydroxybutyrate, and acetoacetate. The monoand 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 organic anion transporters OAT1, OAT2, and OAT3 are involved in the movement of uric acid through the basolateral membrane, although the detailed mechanisms are still being elucidated.


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InternalMed_Harrison. 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 association of the consumption of fructose-sweetened soft drinks with an increased risk of hyperuricemia and gout. Genome-wide association scanning suggests 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). Notably, though, genetic polymorphisms explain only ~6% of the differences


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InternalMed_Harrison. relative risk of developing gout by 30–70%, most likely by increasing expression of the shorter isoform, SLC2A9v2 (GLUT9ΔN). Notably, though, genetic polymorphisms explain only ~6% of the differences in serum uric acid levels in Caucasians. Clearly, gout is polygenic and complex, and at this time the utility of genetic testing for relevant polymorphisms remains investigational and of no clinical utility.


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InternalMed_Harrison. 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. CHAPTER 431e Disorders of Purine and Pyrimidine Metabolism 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. 395.


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. If recognized, uric acid nephropathy is potentially reversible. Appropriate therapy has reduced the mortality rate from ~50% to practically nil. Serum levels cannot be relied on for diagnosis because this condition has developed in the presence of urate concentrations varying from 720 to 4800 μmol/L (12–80 mg/dL). The distinctive feature is the 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.


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InternalMed_Harrison. Metabolic syndrome (Chap. 422) 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 treatment of asymptomatic hyperuricemia does not alter the progression of renal dysfunction in patients with renal disease. An increased risk of stone formation in those with asymptomatic hyperuricemia has not been established.


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InternalMed_Harrison. 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. See Chap. 395 for treatment of gout, including urate nephrosis.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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 below 6.0 mg/dL (357 μmol/L) in <50% of patients; this result suggested that higher doses should be considered. The drug 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 431e-1) include aspirin (at doses >2.0 g/d), losartan, fenofibrate, x-ray contrast materials, and 431e-5 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. (See also Table 431e-3, Table 431e-4, Fig. 431e-3, and Fig. 431e-4) More than 30 defects in human purine and pyrimidine metabolic pathways have been identified thus far. Many are benign, but about half are associated with clinical manifestations, some causing major morbidity and mortality. Advances in genetics, along with high-performance liquid chromatography and tandem mass spectrometry, have facilitated diagnosis.


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InternalMed_Harrison. PURINE DISORDERS HPRT Deficiency The HPRT gene is located on the X chromosome. Affected males are hemizygous for the mutant gene; carrier females are asymptomatic. A complete deficiency of HPRT, the Lesch-Nyhan syndrome, is characterized by hyperuricemia, self-mutilative behavior, choreoathetosis, spasticity, and mental retardation. A partial deficiency of HPRT, the Kelley-Seegmiller syndrome, is associated with hyperuricemia but no central nervous system manifestations. In both disorders, the hyperuricemia results from urate overproduction and can cause uric acid crystalluria, nephrolithiasis, obstructive uropathy, and gouty arthritis. Early diagnosis and appropriate therapy with allopurinol can prevent or eliminate all the problems attributable to hyperuricemia without affecting behavioral or neurologic abnormalities.


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InternalMed_Harrison. Increased PRPP Synthetase Activity Like the HPRT deficiency states, PRPP synthetase overactivity is X-linked and results in gouty arthritis and uric acid nephrolithiasis. Nerve deafness occurs in some families. Adenine Phosphoribosyltransferase (APRT) Deficiency APRT deficiency is inherited as an autosomal recessive trait. Affected individuals develop kidney stones composed of 2,8-dihydroxyadenine. Caucasians with the disorder have a complete deficiency (type I), whereas Japanese CHAPTER 431e Disorders of Purine and Pyrimidine Metabolism


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InternalMed_Harrison. CHAPTER 431e Disorders of Purine and Pyrimidine Metabolism Carbamylphosphate +Aspartic acid Orotic AcidUTP RNA CTP or dCTP RNA or DNA UMPUDPdUMP CMP Cytidine Uracil °-Alanine °-Aminoisobutyric acid TTP 1 2 3 4 5 5 DNA dTMP Thymidine Thymine Uridine 2 FIgURE 431e-4 Abbreviated scheme of pyrimidine metabolism. (1) Thymidine kinase, (2) dihydropyrimidine dehydrogenase, (3) thymidylate synthase, (4) UMP synthase, (5) 5′-nucleotidase. CMP, cytidine-5′-monophosphate; UMP, uridine-5′-monophosphate; UDP, uridine-5′-diphosphate; dUMP, deoxyuridine-5′-monophosphate; dTMP, deoxythymidine-5′-monophosphate; TTP, thymidine triphosphate; UTP, uridine triphosphate. individuals have some measurable enzyme activity (type II). Expression of the defect is similar in the two populations, as is the frequency of the heterozygous state (0.4–1.1 per 100). Allopurinol treatment prevents stone formation.


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InternalMed_Harrison. Hereditary Xanthinuria A deficiency of xanthine oxidase causes all purine in the urine to occur in the form of hypoxanthine and xanthine. About two-thirds of deficient individuals are asymptomatic. The remainder develop kidney stones composed of xanthine. Myoadenylate Deaminase Deficiency Primary (inherited) and secondary (acquired) forms of myoadenylate deaminase deficiency have been described. The primary form is inherited as an autosomal recessive trait. Clinically, some persons may have relatively mild myopathic symptoms with exercise or other triggers, but most individuals with this defect are asymptomatic. Therefore, another explanation for the myopathy should be sought in symptomatic patients with this deficiency. The acquired deficiency occurs in association with a wide variety of neuromuscular diseases, including muscular dystrophies, neuropathies, inflammatory myopathies, and collagen vascular diseases.


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InternalMed_Harrison. Adenylosuccinate Lyase Deficiency Deficiency of this enzyme is due to an autosomal recessive trait and causes profound psychomotor retardation, seizures, and other movement disorders. All individuals with this deficiency are mentally retarded, and most are autistic. Adenosine Deaminase Deficiency and Purine Nucleoside Phosphorylase Deficiency See Chap. 374. The pyrimidine cytidine is found in both DNA and RNA; it is a complementary base pair for guanine. Thymidine is found only in DNA, where it is paired with adenine. Uridine is found only in RNA and can pair with either adenine or guanine in RNA secondary structures. Pyrimidines can be synthesized by a de novo pathway (Fig. 431e-4) or reused in a salvage pathway. Although more than 25 different enzymes are involved in pyrimidine metabolism, disorders of these pathways are rare. Seven disorders of pyrimidine metabolism have been discovered (Table 431e-4), three of which are discussed below.


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InternalMed_Harrison. Orotic Aciduria Hereditary orotic aciduria is caused by mutations in a bifunctional enzyme, uridine-5′monophosphate (UMP) synthase, which converts orotic acid to UMP in the de novo synthesis pathway (Fig. 431e-4). The disorder is characterized by hypochromic megaloblastic anemia that is unresponsive to vitamin B12 and folic acid, growth retardation, and neurologic abnormalities. Increased excretion of orotic acid causes crystalluria and obstructive uropathy. Replacement of uridine (100–200 mg/kg per day) corrects anemia, reduces orotic acid excretion, and improves the other sequelae of the disorder.


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InternalMed_Harrison. Pyrimidine 5′-nucleotidase Deficiency Pyrimidine 5′-nucleotidase catalyzes the removal of the phosphate group from pyrimidine ribonucleoside monophosphates (cytidine5′-monophosphate or UMP) (Fig. 431e-4). An inherited deficiency of this enzyme causes hemolytic anemia with prominent basophilic stippling of erythrocytes. The accumulation of pyrimidines or cytidine diphosphate choline is thought to induce hemolysis. There is no specific treatment. Acquired pyrimidine 5′-nucleotidase deficiency has been reported in lead poisoning and in thalassemia. Dihydropyrimidine Dehydrogenase Deficiency Dihydropyrimidine dehydrogenase is the rate-limiting enzyme in the pathway of uracil and thymine degradation (Fig. 431e-4). Deficiency of this enzyme causes excessive urinary excretion of uracil and thymine. In addition, this deficiency causes nonspecific cerebral dysfunction with convulsive disorders, motor retardation, and mental retardation. No specific treatment is available.


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InternalMed_Harrison. Medication Effect on Pyrimidine Metabolism A variety of medications can influence pyrimidine metabolism. The anticancer agents fluorodeoxyuridine and 5-fluorouracil and the antimicrobial agent fluorocytosine cause cytotoxicity when converted to fluorodeoxyuridylate, a specific suicide inhibitor of thymidylate synthase. Fluorocytosine must be converted to 5-fluorouracil to be effective. This conversion is catalyzed by cytosine deaminase activity. Fluorocytosine’s action is selective because cytosine deaminase is present in bacteria and fungi but not in human cells. Dihydropyrimidine dehydrogenase is involved in the degradation of 5-fluorouracil. Consequently, deficiency of this enzyme is associated with 5-fluorouracil neurotoxicity.


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InternalMed_Harrison. Leflunomide, which is used to treat rheumatoid arthritis, inhibits de novo pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase, resulting in an antiproliferative effect on T cells. Allopurinol, which inhibits xanthine oxidase in the purine metabolic pathway, also inhibits the activity of orotidine-5′-phosphate decarboxylase, a step in UMP synthesis. Consequently, allopurinol use is associated with increased excretion of orotidine and orotic acid. There are no known clinical effects of this inhibition.


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InternalMed_Harrison. Lysosomal Storage Diseases Robert J. Hopkin, Gregory A. Grabowski Lysosomes are heterogeneous subcellular organelles containing specific hydrolyses that allow selective processing or degradation of proteins, nucleic acids, carbohydrates, and lipids. There are more than 40 dif-ferent lysosomal storage diseases (LSDs), classified according to the 432e nature of the stored material (Table 432e-1). Several of the most prevalent disorders are reviewed here: Tay-Sachs disease, Fabry disease, Gaucher disease, Niemann-Pick disease, lysosomal acid lipase deficiencies, the mucopolysaccharidoses, and Pompe disease. LSDs should be considered in the differential diagnosis of patients with neurologic, renal, or muscular degeneration and/or unexplained hepatomegaly, splenomegaly, cardiomyopathy, or skeletal dysplasias and deformations. Physical findings are disease specific, and enzyme assays or genetic testing can be used to make a definitive diagnosis. Although the nosology of LSDs segregates the


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InternalMed_Harrison. dysplasias and deformations. Physical findings are disease specific, and enzyme assays or genetic testing can be used to make a definitive diagnosis. Although the nosology of LSDs segregates the variants into distinct phenotypes, these are heuristic; in the clinic, each disease exhibits—to some degree—a continuous spectrum of manifestations, from severe to attenuated variants.


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InternalMed_Harrison. Lysosomal biogenesis involves ongoing synthesis of lysosomal hydrolases, membrane constitutive proteins, and new membranes. Lysosomes originate from the fusion of trans-Golgi network vesicles with late endosomes. Progressive vesicular acidification accompanies the maturation of these vesicles; this gradient facilitates the pH-dependent dissociation of receptors and ligands and also activates lysosomal hydrolases. Lysosomes are components of the lysosome/autophagy/ mitophagy system, which can be disrupted in the LSDs.


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InternalMed_Harrison. Abnormalities at any biosynthetic step can impair enzyme activation and lead to a lysosomal storage disorder. After leader sequence clipping, remodeling of complex oligosaccharides (including the lysosomal targeting ligand mannose-6-phosphate as well as high-mannose oligosaccharide chains of many soluble lysosomal hydrolases) occurs during transit through the Golgi. Lysosomal integral or associated membrane proteins are sorted to the membrane or interior of the lysosome by several different peptide signals. Phosphorylation, sulfation, additional proteolytic processing, and macromolecular assembly of heteromers occur concurrently. Such posttranslational modifications are critical to enzyme function, and defects can result in multiple enzyme/protein deficiencies.


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InternalMed_Harrison. The final common pathway for LSDs is the accumulation of specific macromolecules within tissues and cells that normally have a high flux of these substrates. The majority of lysosomal enzyme deficiencies result from point mutations or genetic rearrangements at a locus that encodes a single lysosomal hydrolase. However, some mutations cause deficiencies of several different lysosomal hydrolases by alteration of the enzymes/proteins involved in targeting, active site modifications, or macromolecular association or trafficking. All LSDs are inherited as autosomal recessive disorders except for Hunter (mucopolysaccharidosis type II), Danon, and Fabry diseases, which are X-linked. Substrate accumulation leads to lysosomal distortion, which has significant pathologic consequences. In addition, abnormal amounts of metabolites may also have pharmacologic effects important to disease pathophysiology and propagation.


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InternalMed_Harrison. For many LSDs, the accumulated substrates are endogenously synthesized within particular tissue sites of pathology. Other diseases have greater exogenous substrate supplies. For example, they are delivered by low-density lipoprotein receptor–mediated uptake in Fabry and cholesteryl ester storage diseases (CESDs) or by phagocytosis in Gaucher disease type 1. The threshold hypothesis refers to a level of enzyme activity below which disease develops; small changes in enzyme activity near the threshold can lead to or prevent disease. A critical element of this model is that enzymatic activity can be challenged by changes in substrate flux based on genetic background, cell turnover, recycling, or metabolic demands. Thus, a set level of residual 432e-1 enzyme may be adequate for substrate in some tissues or cells but not in others. In addition, several variants of each LSD exist at a clinical level. These disorders therefore represent a continuum of manifestations that are not easily


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InternalMed_Harrison. in some tissues or cells but not in others. In addition, several variants of each LSD exist at a clinical level. These disorders therefore represent a continuum of manifestations that are not easily dissociated into discrete entities. The bases for such variations have not been elucidated in any detail.


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InternalMed_Harrison. About 1 in 30 Ashkenazi Jews is a carrier for Tay-Sachs disease, which is caused by total hexosaminidase A (Hex A) deficiency resulting from defective α-chains. The infantile form is a fatal neurodegenerative disease with macrocephaly, loss of motor skills, increased startle reaction, and a macular cherry red spot. The juvenile-onset form presents as ataxia and dementia, with death by age 10–15 years. The adult-onset disorder is characterized by clumsiness in childhood; progressive motor weakness in adolescence; and additional spinocerebellar and lower-motor-neuron symptoms and dysarthria in adulthood. Intelligence declines slowly, and psychosis is common. Screening for Tay-Sachs disease carriers is recommended in the Ashkenazi Jewish population. Sandhoff disease, due to a deficiency in both Hex A and Hex B resulting from defective β-chains, is phenotypically similar to Tay-Sachs disease but also includes hepatosplenomegaly and bony dysplasias.


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InternalMed_Harrison. Fabry disease is an X-linked disorder that results from mutations in the α-galactosidase A gene. The estimated prevalence of hemizygous males ranges from 1 in 40,000 to 1 in 3500 in selected populations. Clinically, the disease manifests with angiokeratomas (telangiectatic skin lesions), hypohidrosis, corneal and lenticular opacities, acroparesthesia; and progressive small-vessel disease of the kidney, heart, and brain.


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InternalMed_Harrison. The angiokeratomas and acroparesthesias may appear in childhood. Angiokeratomas are punctate, dark red to blue-black, flat or slightly raised, and usually symmetric; they do not blanch with pressure. They range from barely visible to several millimeters in diameter and have a tendency to increase in size and number with age. They usually are most dense between the umbilicus and the knees—the “bathing suit area”—but may occur anywhere, including the mucosal surfaces. Angiokeratomas also occur in several other very rare LSDs. Corneal and lenticular lesions, detectable on slit-lamp examination, may help in establishing a diagnosis of Fabry disease. Debilitating episodic burning pain of the hands, feet, and proximal extremities (acroparesthesia) can last from minutes to days and can be precipitated by changes in temperature, exercise, fatigue, or fever. Abdominal pain can resemble that from appendicitis or renal colic. Proteinuria, isosthenuria, and progressive renal dysfunction occur in


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InternalMed_Harrison. by changes in temperature, exercise, fatigue, or fever. Abdominal pain can resemble that from appendicitis or renal colic. Proteinuria, isosthenuria, and progressive renal dysfunction occur in the second to fourth decades; ~5% of male patients with idiopathic renal failure have α-galactosidase A mutations. Hypertension, left ventricular hypertrophy, anginal chest pain, and congestive heart failure can occur in the third to fourth decades. About 1–3% of patients with idiopathic hypertrophic myocardiopathy have Fabry disease. Similarly, ~3–5% of male patients with idiopathic stroke at 35–50 years of age have α-galactosidase A mutations. Leg lymphedema without hypoproteinemia and episodic diarrhea also occur. Death is due to renal failure or cardiovascular or cerebrovascular disease in untreated male patients. Variants with residual α-galactosidase A activity may have late-onset manifestations that are limited to the cardiovascular system and resemble hypertrophic cardiomyopathy.


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InternalMed_Harrison. untreated male patients. Variants with residual α-galactosidase A activity may have late-onset manifestations that are limited to the cardiovascular system and resemble hypertrophic cardiomyopathy. Variants with predominant cardiac, renal, or central nervous system (CNS) manifestations are becoming better defined. Up to 70% of heterozygous females may exhibit clinical manifestations. However, in females, heart disease is the most common life-threatening manifestation, followed in frequency by stroke and then renal disease.


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InternalMed_Harrison. Phenytoin and carbamazepine diminish chronic and episodic acroparesthesia. Chronic hemodialysis or kidney transplantation can be lifesaving in patients with renal failure. Enzyme therapy clears stored lipids from a variety of cells, particularly those of the renal, cardiac, and skin vascular endothelium. Renal insufficiency appears to be irreversible. Early institution of enzyme therapy may prevent or slow the progression of life-threatening complications. Gaucher disease is an autosomal recessive disorder that results from defective activity of acid β-glucosidase; ~400 mutations have been described at the GBA1 locus of such patients. Disease variants are classified by the absence or presence and progression of neuronopathic involvement.


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InternalMed_Harrison. Gaucher disease type 1 is a nonneuronopathic disease that can present in childhood to adulthood as slowly to rapidly progressive visceral disease. About 55–60% of patients are diagnosed at <20 years of age in white populations and at even younger ages in other groups. This pattern of presentation is distinctly bimodal, with peaks at <10–15 years and at ~25 years. Younger patients tend to have a greater degree of hepatosplenomegaly and accompanying blood cytopenias. In contrast, the older group has a greater tendency for chronic bone disease. Hepatosplenomegaly occurs in virtually all symptomatic patients and can be minor or massive. Accompanying anemia and thrombocytopenia are variable and are not directly related to liver or spleen volumes. Severe liver dysfunction is unusual. Splenic infarctions can resemble an acute abdomen. Pulmonary hypertension and alveolar Gaucher cell accumulation are uncommon but life-threatening and can occur at any age. GBA1 mutations in the heteroor


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InternalMed_Harrison. infarctions can resemble an acute abdomen. Pulmonary hypertension and alveolar Gaucher cell accumulation are uncommon but life-threatening and can occur at any age. GBA1 mutations in the heteroor homozygous state are a significant risk factor for early-onset or more rapidly progressive Parkinson disease.


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InternalMed_Harrison. All patients with Gaucher disease have nonuniform infiltration of bone marrow by lipid-laden macrophages termed Gaucher cells. This phenomenon can lead to marrow packing with subsequent infarction, ischemia, necrosis, and cortical bone destruction. Bone marrow involvement spreads from proximal to distal in the limbs and can involve the axial skeleton extensively, causing vertebral collapse. In addition to bone marrow involvement, bone remodeling is defective, with loss of total bone calcium leading to osteopenia, osteonecrosis, avascular infarction, and vertebral compression fractures and spinal cord involvement. Aseptic necrosis of the femoral head is common, as is fracture of the femoral neck. The mechanism by which diseased bone marrow macrophages interact with osteoclasts and/or osteoblasts to cause bone disease is not well understood. Chronic, ill-defined bone pain can be debilitating and poorly correlated with radiographic findings. “Bone crises” are associated with localized


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InternalMed_Harrison. to cause bone disease is not well understood. Chronic, ill-defined bone pain can be debilitating and poorly correlated with radiographic findings. “Bone crises” are associated with localized excruciating pain and, on occasion, local erythema, fever, and leukocytosis. These crises represent acute infarctions of bone, as evidenced in nuclear scans by localized absent uptake of pyrophosphate agents. Decreased acid β-glucosidase activity (0–20% of normal) in nucleated cells establishes the diagnosis. The enzyme is not present in bodily fluids. The sensitivity of enzyme testing is poor for heterozygote detection; molecular testing by GBA1 sequencing is preferred. The disease frequency varies from about 1 in 1000 among Ashkenazi Jews to <1 in 100,000 in other populations; ~1 in 12–15 Ashkenazi Jews carries a Gaucher disease allele. Four common mutations account for ~85% of the mutations in that population of affected patients: N370S (1226G), 84GG (a G insertion at cDNA position 84), L444P


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InternalMed_Harrison. Jews carries a Gaucher disease allele. Four common mutations account for ~85% of the mutations in that population of affected patients: N370S (1226G), 84GG (a G insertion at cDNA position 84), L444P (1448C), and IVS-2 (an intron 2 splice junction mutation).


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InternalMed_Harrison. Genotype/phenotype studies indicate a significant, though not absolute, correlation between disease type and severity and the GBA1 genotype. The most common mutation in the Ashkenazi Jewish population (N370S) shares a 100% association with nonneuronopathic or type 1 Gaucher disease. The N370S/N370S and N370S/other mutant allele genotypes are associated with later-onset/less severe disease and with earlier-onset/severe disease, respectively. As many as 50–60% of individuals with the N370S/N370S genotype are asymptomatic. Other alleles include L444P (very low activity), 84GG (null), or IVS-2 (null) and rare/private or uncharacterized alleles. The L444P/L444P patients almost always have life-threatening to very severe/early-onset disease, and many, though not all, develop CNS involvement in the first two decades of life. Symptom-based treatment of blood cytopenias and joint replacement surgeries continue to have important roles in management.


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InternalMed_Harrison. Symptom-based treatment of blood cytopenias and joint replacement surgeries continue to have important roles in management. However, regular intravenous enzyme therapy is currently the treat-432e-5 ment of choice in significantly affected patients and is highly efficacious and safe in diminishing hepatosplenomegaly and improving hematologic values. Bone disease is decreased but not eliminated by enzyme therapy. Adult patients may benefit from adjunctive treatment with bisphosphonates to improve bone density. Patients who cannot be treated with enzyme, either because it is not effective or because they have an allergy or other hypersensitivities, may be receive substrate reduction therapy with medications that decrease the production of the complex lipid molecules that are broken down by acid β-glucosidase.


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InternalMed_Harrison. Gaucher disease type 2 is a rare, severe, progressive CNS disease that leads to death by 2 years of age. Gaucher disease type 3 has highly variable manifestations in the CNS and viscera. It can present in early childhood with rapidly progressive, massive visceral disease and slowly progress to static CNS involvement; in adolescence with dementia; or in early adulthood with rapidly progressive, uncontrollable myoclonic seizures and mild visceral disease. Visceral disease in type 3 is nearly identical to that in type 1 but is generally more severe. Early CNS findings may be limited to defects in lateral gaze tracking, which may remain static for decades. Mental retardation can be slowly progressive or static. This variant is most frequent among individuals of Swedish descent. Visceral—but not CNS—involvement responds to enzyme therapy.


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InternalMed_Harrison. Niemann-Pick diseases are autosomal recessive disorders that result from defects in acid sphingomyelinase. Types A and B are distinguished by the early age of onset and progressive CNS disease in type A. Type A typically has its onset in the first 6 months of life, with rapidly progressive CNS deterioration, spasticity, failure to thrive, and massive hepatosplenomegaly. Type B has a later, more variable onset and is characterized by a progression of hepatosplenomegaly, with eventual development of cirrhosis and hepatic replacement by foam cells. Affected patients develop progressive pulmonary disease with dyspnea, hypoxemia, and a reticular infiltrative pattern on chest x-ray. Foam cells are present in alveoli, lymphatic vessels, and pulmonary arteries. Progressive hepatic or lung disease leads to death in adolescence or early adulthood.


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InternalMed_Harrison. The diagnosis is established by markedly decreased (1–10% of normal) sphingomyelinase activity in nucleated cells. There is no specific treatment for Niemann-Pick disease. The efficacy of hepatic or bone marrow transplantation has not been clearly established. Clinical trials of enzyme therapy are in phases 2 and 3. Niemann-Pick C diseases are progressive CNS diseases due to mutations in either NPC1 or NPC2. They present with liver or splenic disease, but their major manifestations are progressive CNS disease over one to two decades. Treatment with substrate inhibition agents (e.g., Miglustat) and substrate depletion with cyclodextrin have shown promise.


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InternalMed_Harrison. Lysosomal acid lipase deficiency may result in Wolman disease (severe deficiency) or CESD, which presents later and has some (3–10%) residual enzyme activity. Wolman disease presents in early infancy with hepatosplenomegaly, diarrhea, vomiting, and abdominal distention, sometimes accompanied by adrenal calcification, anemia, and mixed hyperlipidemia. Death occurs before the age of 1 year and is often due to severe intestinal malabsorption. CESD is heterogeneous and presents with hepatomegaly and hepatosteatosis at any age in childhood or adulthood. CESD should be included in the differential diagnosis for all patients with isolated hypercholesterolemia. The disease may progress to hepatic fibrosis, cirrhosis, and liver failure. In addition, patients often develop very early-onset atherosclerotic vascular disease, which may be life-threatening in childhood. Preliminary results of treatment with enzyme replacement therapy are promising for Wolman disease and CESD.


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InternalMed_Harrison. Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by deficiency of α-L-iduronidase. The continuum of involvement traditionally has been divided into three categories: (1) Hurler disease (MPS I H) for severe deficiency with neurodegeneration, (2) Scheie disease (MPS I S) for later-onset disease without neurologic involvement and with relatively less severe disease in other organ systems, and (3) Hurler-Scheie syndrome (MPS I H/S) for patients intermediate between these extremes. MPS I H/S is characterized by severe somatic disease, usually without overt neurologic deterioration. MPS I often presents in infancy or early childhood as chronic rhinitis, clouding of the corneas, and hepatosplenomegaly. As the disease progresses, nearly every organ system can be affected. In the more severe forms, cardiac and respiratory diseases become life-threatening in childhood. Skeletal disease can be quite severe, resulting in very limited mobility.


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InternalMed_Harrison. There are two current treatments for the MPS I diseases. Hematopoietic stem cell transplantation (HSCT) is the standard treatment for patients presenting at <2 years of age who appear to have or are at risk for neurologic degeneration. HSCT results in stabilization of CNS disease and reverses hepatosplenomegaly. It also beneficially affects cardiac and respiratory disease. HSCT does not eliminate corneal disease or result in the resolution of progressive skeletal disease. Enzyme therapy effectively addresses hepatosplenomegaly and alleviates cardiac and respiratory disease. The enzyme does not effectively penetrate the CNS and does not directly affect CNS disease. Enzyme therapy and HSCT appear to have similar effects on visceral signs and symptoms. Enzyme therapy poses a lower risk of life-threatening complications and may therefore be advantageous for patients who have attenuated manifestations without CNS disease. A combination of enzyme therapy and HSCT has been used, with enzyme


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InternalMed_Harrison. complications and may therefore be advantageous for patients who have attenuated manifestations without CNS disease. A combination of enzyme therapy and HSCT has been used, with enzyme therapy initiated prior to transplantation in an attempt to reduce the disease burden. The experience with this approach is not well documented, but it appears to have advantages over HSCT alone.


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InternalMed_Harrison. U.S. Food and Drug Administration (FDA) approval. This very rare autosomal recessive disorder is characterized by hepatosplenomegaly, bone disease, heart disease, and respiratory compromise similar to those seen in MPS I; however, MPS VI is due to deficiency of arylsulfatase B and is not associated with neurologic degeneration. Hunter disease (MPS II) is an X-linked disorder due to deficiency in iduronate sulfate sulfatase and has manifestations similar to those of MPS I, including neurologic degeneration. There is no corneal clouding or other eye disease. Like MPS I, MPS II is clinically variable, with CNS and non-CNS variants. HSCT has not been successful in treating CNS disease associated with MPS II. The FDA and the European Medicines Agency (EMA) have approved enzyme therapy for the visceral manifestations of MPS II.


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InternalMed_Harrison. Acid maltase (acid α-glucosidase, GAA) deficiency, also called Pompe disease, is the only glycogen LSD. The classic severe infantile form presents with hypotonia, myocardiopathy, and hepatosplenomegaly. This variant is rapidly progressive and generally results in death in the first year of life. However, as with other LSDs, there are earlyand late-onset forms of this disorder. The late-onset variants may be as common as 1 in 40,000; patients typically present with a slowly progressive myopathy that may resemble limb-girdle muscular dystrophy. Respiratory insufficiency may be the presenting sign or may develop with advancing disease. In late stages of the disease, patients may require mechanical ventilation, report swallowing difficulties, and experience loss of bowel and bladder control. Myocardiopathy is not usually seen in late-onset variants of Pompe disease.


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InternalMed_Harrison. The FDA and EMA have approved enzyme therapy for Pompe disease. This treatment clearly prolongs life in the infantile form, consistently resulting in improved cardiac function. Respiratory function is also improved in most treated infants. Some infants demonstrate marked improvement in motor functions, while others have minor changes in muscle tone or strength. Prevention of deterioration has been shown with GAA enzyme therapy in the late-onset forms. Early intervention with GAA enzyme therapy in such patients may limit or prevent deterioration, but very advanced disease will have significant irreversible components.


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InternalMed_Harrison. Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism Priya S. Kishnani, Yuan-Tsong Chen Carbohydrate metabolism plays a vital role in cellular function by pro-433e viding the energy required for most metabolic processes. The relevant biochemical pathways involved in the metabolism of these carbohydrates are shown in Fig. 433e-1. Glucose is the principal substrate of energy metabolism in humans. Metabolism of glucose generates ATP through glycolysis and mitochondrial oxidative phosphorylation. The body obtains glucose through the ingestion of polysaccharides (primarily starch) and disaccharides (e.g., lactose, maltose, and sucrose). Galactose and fructose are two other monosaccharides that serve as sources of fuel for cellular metabolism; however, their role as fuel sources is much less significant than that of glucose. Galactose is derived from lactose (galactose + glucose), which is found in milk products, and is an important component of certain


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InternalMed_Harrison. role as fuel sources is much less significant than that of glucose. Galactose is derived from lactose (galactose + glucose), which is found in milk products, and is an important component of certain glycolipids, 433e-1 glycoproteins, and glycosaminoglycans. Fructose is found in fruits, vegetables, and honey. Sucrose (fructose + glucose) is another dietary source of fructose and is a commonly used sweetener.


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InternalMed_Harrison. Debrancher PaP PbKa PbKb Pb Pa ˜-Glucosidase Glucose + Pi ENDOPLASMIC RETICULUM Glucose LYSOSOME Brancher PaP Pa Pb GSa GSa UTP UDP-Gal Gal-1-P Uridyl transferase GSb Phosphoglucomutase Glucokinase, hexokinase Glc-1-P Gal-1-P UDP-Glc Pyrophosphorylase UDP-Gal-4-epimerase Galactose Galacto-kinase Fructose UDP-Glc Glc-6-PGlc-6-P F-6-P F-1, 6-P2 Glyceraldehyde-3-P 1, 3-Bisphosphoglycerate 3-Phosphoglycerate 2-Phosphoglycerate Phosphoenolpyruvate Dihydroxyacetone-P Phosphotriose isomerase Glyceraldehyde Aldolase Phosphohexose isomerase Phosphofructokinase Fructose 1,6-diphosphatase Aldolase Glyceraldehyde-3-P dehydrogenase Phosphoglycerate kinase Phosphoglycerate mutase Enolase Pyruvate kinase Lactate dehydrogenase Pyruvate Lactate NADHTCA Cycle CYTOSOL NAD GSb PbKa PbKb G CYTOSOL G G G G G Galactose GLUT2 Glucose Trans-locase GLUT2 GLUT2 Glucose Glucose Fructose F-1-P GLUT2 MITOCHONDRIA Glc-6-Pase FIGuRE 433e-1 Metabolic pathways related to glycogen storage diseases and galactose and


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InternalMed_Harrison. G Galactose GLUT2 Glucose Trans-locase GLUT2 GLUT2 Glucose Glucose Fructose F-1-P GLUT2 MITOCHONDRIA Glc-6-Pase FIGuRE 433e-1 Metabolic pathways related to glycogen storage diseases and galactose and fructose disorders. Nonstandard abbreviations are as follows: GS ainactive glycogen synthase; Pa, active phosphorylase; Pb, inactive phosphorylase; P


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InternalMed_Harrison. Glycogen, the storage form of glucose in animal cells, is composed of glucose residues joined in straight chains by α1-4 linkages and branched at intervals of 4–10 residues by α1-6 linkages. Glycogen forms a treelike molecule and can have a molecular weight of many millions. Glycogen may aggregate to form structures recognizable by electron microscopy. With the exception of type 0 disease, defects in glycogen metabolism typically cause an accumulation of glycogen in the tissues—hence the designation glycogen storage diseases (GSDs). The structure of stored glycogen can be normal or abnormal in the various disorders. Defects in gluconeogenesis or glycolytic pathways, including galactose and fructose metabolism, usually do not result in glycogen accumulation.


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InternalMed_Harrison. Clinical manifestations of the various disorders of carbohydrate metabolism differ markedly. The symptoms range from harmless to lethal. Unlike disorders of lipid metabolism, mucopolysaccharidoses, or other storage diseases, many carbohydrate disorders have been effectively managed with dietary therapy. All of the genes responsible for inherited defects of carbohydrate metabolism have been cloned, and mutations have been identified. Advances in our understanding of the molecular basis of these diseases are being used to improve diagnosis and management. Some of these disorders are candidates for enzyme replacement therapy, substrate reduction therapy, and early trials of gene therapy.


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InternalMed_Harrison. Historically, the GSDs were categorized numerically in the order in which the enzymatic defects were identified. They are also classified by the organs involved (liver, muscle, and/or heart) and clinical manifestations. The latter is the system followed in this chapter (Table 433e-1). The overall frequency of all forms of GSD is ~1 in 20,000 live births. Most are inherited as autosomal recessive traits; however, phosphoglycerate kinase deficiency—one form of liver phosphorylase kinase (PhK) deficiency—and lysosomal-associated membrane protein 2 (LAMP2) deficiency are X-linked disorders. The most common childhood disorders are glucose-6-phosphatase deficiency (type I), lysosomal acid α-glucosidase deficiency (type II), debrancher deficiency (type III), and liver PhK deficiency (type IX). The most common adult disorder is myophosphorylase deficiency (type V, or McArdle disease).


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InternalMed_Harrison. DISORDERS WITH HEPATOMEGALY AND HYPOGLYCEMIA Type I GSD (Glucose-6-Phosphatase or Translocase Deficiency, Von Gierke’s Disease) Type I GSD is an autosomal recessive , active glycogen synthase; GS , disorder caused by glucose-6-phospha aP, phosphorylase tase deficiency in liver, kidney, and intes- CHAPTER 433e Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism α phosphatase; PbKa, active phosphorylase β kinase; PbKb, inactive phosphorylase β kinase; G, gly-tinal mucosa. There are two subtypes of cogenin, the primer protein for glycogen synthesis. (Modified from AR Beaudet, in KJ Isselbacher et al GSD I: type Ia, in which the glucose[eds]: Harrison’s Principles of Internal Medicine, 13th ed., New York, McGraw-Hill, 1994, p 1855.) 6-phosphatase enzyme is defective, and Disorders with hepatomegaly and hypoglycemia Disorders with liver cirrhosis


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InternalMed_Harrison. Disorders with hepatomegaly and hypoglycemia Disorders with liver cirrhosis Growth retardation, enlarged liver and kidney, hypoglycemia, elevated blood lactate, cholesterol, triglycerides, and uric acid As for Ia, with additional findings of neutropenia and neutrophil dysfunction Childhood: hepatomegaly, growth retardation, muscle weakness, hypoglycemia, hyperlipidemia, elevated liver aminotransferases. Liver symptoms improve with age. Adulthood: muscle atrophy and weakness; onset in third or fourth decades; variable cardiomyopathy, liver cirrhosis, progressive liver failure Liver symptoms same as in type IIIa; no muscle symptoms Hepatomegaly, variable hypoglycemia, hyperlipidemia, and ketosis. Symptoms may improve with age. Fasting hypoglycemia and ketosis, elevated lactic acid and hyperglycemia after glucose load, no hepatomegaly


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InternalMed_Harrison. Fasting hypoglycemia and ketosis, elevated lactic acid and hyperglycemia after glucose load, no hepatomegaly Failure to thrive, short stature, hypophosphatemic rickets, metabolic acidosis, hepatomegaly, proximal renal tubular dysfunction, impaired glucose and galactose utilization Common, severe hypoglycemia. Complications in adulthood include hepatic adenomas, hepatic carcinoma, and renal failure. ~10% of type I Common, intermediate severity of hypoglycemia. Hepatic adenomas, liver cirrhosis, and hepatic carcinoma can occur. ~15% of type III Rare, often a “benign” glycogenosis, severe cases being recognized Common, X-linked, typically less severe than autosomal forms; clinical variability within and between subtypes; severe cases being recognized Rare, consanguinity in 70% Fructose 1,6-bisphosphate aldolase A deficiency Fructose 1,6-bisphosphate aldolase A


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InternalMed_Harrison. Rare, consanguinity in 70% Fructose 1,6-bisphosphate aldolase A deficiency Fructose 1,6-bisphosphate aldolase A Muscle β-enolase Exercise intolerance, muscle cramps, myoglobinuria on strenuous exercise, increased CK, “second-wind” phenomenon As for type V, with additional findings of compensated hemolysis, myalgia As for type V, with additional findings of hemolytic anemia and CNS dysfunction As for type V, with additional findings of erythematous skin eruption and uterine stiffness resulting in childbirth difficulty in females As for type V, with additional finding of hemolytic anemia As for type V. Some patients may have muscle weakness and atrophy. Disorders with progressive skeletal muscle myopathy and/or cardiomyopathy Common, male predominance Prevalent in Ashkenazi Jews and Japanese Rare, X-linked Rare, most patients African American Rare Rare Rare Rare, autosomal recessive Rare


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InternalMed_Harrison. Common, male predominance Prevalent in Ashkenazi Jews and Japanese Rare, X-linked Rare, most patients African American Rare Rare Rare Rare, autosomal recessive Rare Danon’s disease Lysosomal-associated membrane protein 2 (LAMP2) Infantile: hypotonia, muscle weakness, cardiac enlargement and failure, fatal early late onset (juvenile and adult): progressive skeletal muscle weakness and atrophy, proximal muscle and respiratory muscle seriously affected Severe cardiomyopathy and early heart failure (9–55 years). Congenital fetal form is rapidly fatal with hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome. Severe cardiomyopathy and heart failure (8–15 years) Common, undetectable or very low level of enzyme activity in infantile form; variable residual enzyme activity in late-onset form Very rare, autosomal dominant Very rare, X-linked Abbreviations: CK, creatine kinase; CNS, central nervous system; M, muscle.


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InternalMed_Harrison. Very rare, autosomal dominant Very rare, X-linked Abbreviations: CK, creatine kinase; CNS, central nervous system; M, muscle. type Ib, in which the translocase that transports glucose-6-phosphate across the microsomal membrane is defective. The defects in both subtypes lead to inadequate conversion of glucose-6-phosphate to glucose in the liver and thus make affected individuals susceptible to fasting hypoglycemia.


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InternalMed_Harrison. CliniCal and laboratory findings Persons with type I GSD may develop hypoglycemia and lactic acidosis during the neonatal period; however, more commonly, they exhibit hepatomegaly at 3–4 months of age. Hypoglycemia, hypoglycemic seizures, and lactic acidosis can develop after a short fast. These children usually have doll-like faces with fat cheeks, relatively thin extremities, short stature, and a protuberant abdomen that is due to massive hepatomegaly. The kidneys are enlarged, but the spleen and heart are of normal size. The hepatocytes are distended by glycogen and fat, with large and prominent lipid vacuoles. Despite hepatomegaly, liver enzyme levels are usually normal or near normal. Easy bruising and epistaxis are associated with a prolonged bleeding time as a result of impaired platelet aggregation/adhesion. Hyperuricemia is present. Hyperlipidemia includes elevation of triglycerides, low-density lipoproteins, and phospholipids. Type Ib patients have additional findings of