Nephrol Dial Transplant (2001) 16: 2095-2096
© 2001 European Renal Association-European Dialysis and Transplant Association
Nephroquiz for the Beginner
Ulcerating subcutaneous nodules and advanced renal failure: is it time for a new liver?
(Section Editor: M. G. Zeier)
1Department of Internal Medicine 2Department of Pathology, Hospital of the University of Pennsylvania School of Medicine, Philadelphia, USA
Case
A 40-year-old woman presented to an ambulatory clinic complaining of 'flu-like symptoms. In the past few years she had experienced intermittent Raynaud's phenomenon and claudication symptoms. Her past medical history was significant for nephrolithiasis at age 16, and pathological fractures of both ankles in her early 30s. On laboratory evaluation, she was found to be anaemic, with a haematocrit of 0.25 and mean corpuscular volume of 86 fl, and she had a markedly elevated serum creatinine level of 407 µmol/l. Despite a renal failure diet and therapy with phosphorus binders, her renal function deteriorated rapidly over the next few weeks and she began receiving haemodialysis. A renal biopsy revealed acute interstitial nephritis and the presence of calcium oxalate crystals (Figure 1
).
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Two months later, the patient developed a livedo reticularis rash and painful subcutaneous nodules on the extremities. Several of these lesions subsequently ulcerated and became necrotic (Figure 2
). Despite therapy with pentoxifylline and peripherally acting calcium channel blockers, she soon required bilateral toe amputation for gangrene resulting from vascular insufficiency. Biopsy of the skin lesions revealed calcium oxalate deposition. She subsequently developed intractable nausea and emesis, resulting in a 28-kg weight loss over 4 months, with minimal response to anti-emetics, promotility agents, and a gastroparesis diet. She had a normal upper endoscopy and nuclear medicine gastric emptying study, but abdominal Doppler ultrasonography with colour flow revealed elevated velocities consistent with mild stenosis of the mesenteric vasculature. She also developed gradual dyspnoea on exertion, and orthopnoea with evidence of pulmonary oedema on physical examination. An echocardiogram revealed a dilated, infiltrative cardiomyopathy with an ejection fraction of 35%.
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Questions
What is the likely diagnosis? What definitive test is needed to establish the diagnosis? How would you manage the patient at this time?
Answer to quiz on preceding page
A liver biopsy was performed, which revealed normal hepatic architecture. A biochemical assay for alanine: glyoxalate aminotransferase (AGT) demonstrated a mild deficiency with normal activity of the enzyme, but immunoelectron miscroscopy revealed localization of AGT in the hepatocyte mitochondria rather than in the peroxisomes. The patient was diagnosed with primary hyperoxaluria type 1, and was started promptly on pyridoxine in addition to dietary restriction of oxalate-rich foods. Because of her rapid and inexorable clinical deterioration, she underwent synchronous liver and kidney transplantation, from which she is presently recovering.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder characterized by increased hepatic synthesis and urinary excretion of oxalate. Most patients develop recurrent calcium oxalate nephrolithiasis during childhood, resulting in end-stage renal disease and death in untreated cases [1]. Accumulation of insoluble oxalate throughout the body (systemic oxalosis) is accelerated once the glomerular filtration rate falls to below 20–40 ml/min/1.73 m2, and often involves the bone, arteries, heart, nerves, skin, joints, and eyes [2]. The disease is due to a functional defect of the liver-specific peroxisomal alanine:glyoxalate aminotransferase (AGT). AGT is normally responsible for the transamination of glyoxalate to glycine; a deficiency in this enzyme leads to increased oxidation of glyoxalate to the poorly soluble end-product oxalate [1,2].
The definitive diagnosis of PH1 is made by percutaneous hepatic needle biopsy to assess for AGT catalytic activity [3]. As in our patient, however, 30% of patients with PH1 have normal AGT activity, but have a mutation that alters the quaternary structure of the enzyme such that it is targeted to hepatocyte mitochondria, where it is inactive, instead of to peroxisomes [4]. Therefore, in cases of normal AGT activity, the intracellular distribution (i.e. peroxisomal vs mitochondrial) of AGT must be documented by immunoelectron microscopy.
As soon as the diagnosis of PH1 is suspected, patients should be instructed to maintain a high fluid intake (>2 litres/m2/day) and to restrict oxalate-rich foods in the diet, including strawberries, spinach, rhubarb, coffee, tea, and nuts [2]. Medical therapies of proven benefit include sodium citrate and orthophosphate, which are inhibitors of calcium oxalate crystallization, and pyridoxine, a cofactor of AGT [5]. The prognosis for patients with PH1 and advanced renal failure has improved dramatically since the advent of synchronous liver and kidney transplantation [6]. The transplanted liver provides a functioning copy of the enzyme needed for proper metabolism of oxalate. Clinical outcomes are improved when the diagnosis of PH1 is made early in the course of the disease, thereby allowing the transplant procedure to be performed while the native kidney retains substantial function, and prior to significant extrarenal involvement [2].
Notes
Supported by an educational grant from
References
- Wandzilak TR, Williams HE. The hyperoxaluric syndromes. Endocrinol Metabol Clin North Am1990; 19: 851–867[Web of Science][Medline]
- Cochat P. Primary hyperoxaluria type 1. Kidney Int1999; 55: 2533–2547[Web of Science][Medline]
- Danpure CJ, Jennings PR, Watts RWE. Enzymological diagnosis of primary hyperoxaluria type 1 by measurement of hepatic alanine:glyoxalate aminotransferase activity. Lancet1987; 1: 289–291[Web of Science][Medline]
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Watts RWE. The third workshop on primary hyperoxaluria. Nephrol Dial Transplant1995; 10 [Suppl 8]: 1–2
[Free Full Text] -
Milliner DS, Eickholt JT, Bergstrahl EJ, Wilson DM, Smith LH. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med1994; 331: 1553–1558
[Abstract/Free Full Text] - Watts RWE, Rolles K, Morgan SH et al. Successful treatment of primary hyperoxaluria type 1 by combined hepatic and renal transplantation. Lancet1987; 2: 474–475[Web of Science][Medline]
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