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Persistent cutaneous manifestations of hyperoxaluria after combined hepatorenal transplantation

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Persistent cutaneous manifestations of hyperoxaluria after combined hepatorenal transplantation
Melissa C Rubenstein MD a, Paul T Martinelli MD a, Ilene B Bayer-Garner MD d, Michael J Klebuc MD c, Jonathan L Curry MDa,b, Sylvia Hsu MD a
Dermatology Online Journal 10 (1): 10

Departments of Dermatology (a), Pathology (b), and Plastic Surgery (c) Baylor College of Medicine, Houston, and from the Marshfield Clinicd.


A 30-year-old woman with primary hyperoxaluria type I (PHI) developed livedo reticularis with overlying ulcerations on her legs 16 months after receiving a liver-kidney transplant. A skin biopsy of the lesion showed deposits of calcium oxalate. To our knowledge, there have been no reported cases of livedo reticularis in patients with PH1 after a combined liver-kidney transplant.


Primary hyperoxaluria is a rare congenital disorder of oxalate metabolism characterized by deposits of oxalate in several organs, including the skin. Oxalate deposition in the skin can contribute to livedo reticularis, ulceration, and distal ischemia. Symptoms of systemic oxalosis in patients with PH1 are often ameliorated or corrected with a hepato-renal transplant, which is considered curative therapy. In this report we present a female with PH1 presenting with livedo reticularis and ischemic cutaneous ulcerations in her lower extremities 16 months after undergoing a successful orthotopic liver-kidney transplant.


A Latin-American woman, with a history of primary hyperoxaluria, was admitted in July 2002 for debridement of necrotic ulcers on her lower extremities. The patient reported that her skin lesions first began in 1999 as a lacy red rash on her legs, appearing after she experienced symptoms consistent with Raynaud phenomenon in her toes. The lesions proceeded to ulcerate and she developed paresthesias in her lower extremities. Plasmapheresis successfully cleared the lesions. She had been doing well from a cutaneous standpoint until similar ulcerations re-appeared on her legs approximately 6 months ago. Various treatment methods, including enzymatic debridements with Accuzyme™ and hyperbaric oxygen therapy, were employed without success.

The patient's past medical history is significant for primary hyperoxaluria type 1 (PH1). As a child she experienced recurrent urolithiasis, with her first episode occurring at the age of 4.

In December 1998 she presented with nausea, vomiting, and decreased urine output, and was diagnosed with renal failure. A renal biopsy showed nephrocalcinosis. Hemodialysis was initially used to treat her renal failure until peritoneal dialysis was begun 1 month later. She was maintained on dialysis until a simultaneous right cadaveric renal transplant and an orthotopic hepatic transplant were performed in August 2001. Additional relevant past surgical history includes sternotomy with removal of a right atrial calcium oxalate crystal in September 1999 after the patient developed chest pain, palpitations, and dyspnea.

The patient has no family history of liver or kidney disease and no family history of similar cutaneous problems. She has 3 children, ages 8, 5, and 4, all of whom are healthy.

Physical examination revealed multiple painful necrotic ulcerations, some with overlying dark eschars, involving the lower legs and dorsal surfaces of the feet. A net-like red-blue discoloration of the skin, consistent with livedo reticularis, was present on her thighs (Fig. 1) lower legs, and ankles.

Figure 1 Figure 2
Ulcer with overlying eschar and surrounding livedo reticularis. (Fig. 1)
Oxalate crystals deposited as large nodules within the substance of the subcuticular tissue are present. (original magnification 20X) (Fig. 2)

The patient was admitted for debridement, and potential grafting of the cutaneous lesions. During a 5-week hospitalization, she received 16 plasma exchanges.

Laboratory evaluation revealed an elevated urinary oxalate level of 91 mg/dL (ref 4-31 mg/dL) and an undetectable serum oxalate level. No additional laboratory abnormalities were found.

The patient underwent surgical debridement of her right lower extremity ulcers and tangential excision of large eschars present on her right leg followed by xenograft placement. A skin biopsy showed full-thickness necrosis of the epidermis with oxalate crystals present in subcuticular blood vessels as well as oxalate crystals deposited as large nodules within the substance of the subcuticular tissue (Fig. 2). Subsequently, a split thickness autograft was harvested from the right leg and placed over a portion of the wound, with a xenograft covering the residual areas. This was done to determine if a graft would adhere and the wound would heal, before attempting to treat a larger area. One week post-procedure, the grafted area was well maintained with no evidence of necrosis. The patient was discharged and scheduled for outpatient plastic surgery followup to assess wound healing and to schedule the next graft. During the 4-month followup, her skin was doing well. Unfortunately, she then expired from cardiac complications of her disease.


Primary hyperoxalurias are a rare group of autosomal-recessive inherited metabolic disorders that cause accumulation of oxalate throughout the body. There are several types of primary hyperoxaluria, two of which have a specific enzyme deficiency. Type I is associated with deficiency of alanine-glyoxalate aminotransferase (AGT), a hepatic peroxisomal enzyme responsible for the detoxification of glyoxalate via conversion to glycine [1]. The deficiency of AGT maps to chromosome 2 q36-37. Several point mutations of the AGT gene have been described [2, 3, 4], some of which are mislocational in that they misdirect the normally peroxismal enzyme to the mitochondria, rendering it nonfunctional; others cause interperoxismal AGT aggregation; and still others render the enzyme catalytically inactive [2, 4, 5, 6]. Type-II hyperoxaluria is far less common and is believed to be due to enzymatic deficiency of D-glycerate dehydrogenase and glycosylate reductase [7]. Type-III hyperoxaluria is due to increased intestinal absorption of oxalate in the absence of intestinal disease. Secondary or acquired hyperoxaluria results from excess intake of oxalate or oxalate precursors (ethylene oxide poison, methoxyflurane anesthesia, or large doses of ascorbic acid), pyridoxine deficiency, and in patients with intestinal disease or those status-post ileal resection. It may also occur in the setting of acute and chronic renal failure.

The hyperoxaluric disorders all result in increased production and consequent urinary excretion of oxalate, a nonmetabolic end product of glyoxalate metabolism. The initial oxalosis in primary hyperoxaluria is confined to the kidneys where the clearance of oxalate occurs, and manifests with stone formation, interstitial nephritis, and ultimately renal failure. In PH1, most patients present with renal colic or nephrolithiasis in childhood. Less commonly, the disease may present in infants with nephrocalcinosis-associated acute renal failure, or in adults (as late as the sixth decade) with renal failure, nephrocalcinosis, or with signs of systemic oxalosis [8, 9].

Once significant renal insufficiency develops, the kidneys are no longer able to maintain a negative oxalate balance and calcium oxalate crystal deposition occurs in various tissues throughout the body including skin and adipose tissue, blood vessels, heart, eyes, central nervous system, thyroid, peripheral nerves, lungs, teeth, joints, synovial fluid, and spleen [8, 10]. Skin involvement is extremely rare. To our knowledge, there are only twelve reported cases of primary hyperoxaluria with livedo reticularis in the literature. The pathogenesis of the livedo reticularis may be attributed to small-vessel ischemia resulting from intravascular oxalate deposition [8, 11, 12]. The vascular insufficiency predisposes the patients to painful, violaceous plaques and tissue necrosis, nonhealing black eschars, ulcers, gangrene, Raynaud phenomenon, subungual nodules, and small papules on the fingertips [8, 10, 11, 13].

In contrast to patients with primary hyperoxaluria, patients with systemic oxalosis of chronic renal failure are more likely to present with extravascular calcified deposits of the skin, including dermal and subcutaneous nodules, tender subungual nodules, and skin-colored to yellow macules and papules usually in an acral distribution or on the face. In addition, the cutaneous ulcerated lesions may clinically mimic those seen in calciphylaxis, an uncommon and generally fatal condition usually observed in the setting of end stage renal disease with secondary hyperparathyroidism [13]. A biopsy specimen of the skin will distinguish between calciphylaxis and oxalosis.

Histologic evaluation of the skin biopsy in a patient with livedo reticularis may be of great diagnostic value. In a patient with oxalosis, the vessel walls contain strongly birefringent yellow-brown crystals, usually unstained, in hematoxylin and eosin sections [13]. In contrast, a skin biopsy of calciphylaxis shows basophilic calcium salt deposits within vessel walls and in the interstitium. Laboratory evaluation of urinary oxalate levels may corroborate the diagnosis of hyperoxaluria. A 24-hour urine collection demonstrating elevated glycolate levels and oxalate can be used to diagnose patients with PH 1. Concomitant hyperoxaluria and hyperglycolic aciduria are also indicative of PH 1, but not all patients with PH1 have hyperglycolic aciduria [6]. The use of urine levels for diagnosis becomes less accurate and more difficult when the glomerular filtration rate drops below 10 ml/min [11]. A definitive diagnosis of PH1 may be made with a liver biopsy that demonstrates reduced, absent, or misplaced catalytic activity of AGT [4].

The natural course of PH1 may be relentless and progressive. Without treatment, nearly one-third of patients will die in 2 years, and death usually occurs before the age of 20 years. Early treatment consists of supportive therapy to keep the urine oxalate and calcium concentrations low. This can be achieved by preventing crystal formation with the use of calcium oxalate crystallization inhibitors (sodium or potassium citrate) or orthophosphate while maintaining a high fluid intake (> 2 liters/m²/day) [14]. A combination of loop- and thiazide-diuretics can also help reduce the urinary calcium concentration [15]. Pyridoxal phosphate is the cofactor for alanine and glyoxylate amino transferase. In PH1, administration of therapeutic doses of pyridoxine may reduce urinary excretion of oxalate. Approximately 25 percent of patients will be sensitive to this vitamin cofactor [4, 14].

Despite supportive therapy, most patients eventually develop renal failure. Treatment with renal transplantation alone is largely unsuccessful and has yielded high failure rates [11, 16]. Kidney transplantation combined with a liver transplant is considered the gold standard of therapy and is the best therapeutic option for patients with PH1 who have reached end-stage renal disease and are unresponsive to pyridoxine [16]. Long-term survival is achieved by correcting the underlying liver defect while simultaneously replacing the damaged kidney. Data from the PH 1 European Transplant Registry Report of 61 patients receiving liver-kidney transplants demonstrated survival rates approaching 80 percent and 70 percent at 5 and 10 years, respectively [17].

After combined transplantation, plasma oxalate levels return to normal before urinary oxalate excretion does. Urinary oxalate may remain elevated for several months or even years post transplantation [17]. The amount of oxalate excretion depends on the amount of mobilized body oxalate stores as well as the ability of the transplanted kidney to excrete the increased amount of oxalate. Because of the increased oxalate burden, patients are aggressively dialyzed during the pretransplantation and early posttransplantation period in order to reduce total body oxalate stores and prevent crystallization within the transplant kidney [18].

The underlying mechanism of the development of livedo reticularis post-transplant in our patient may only be speculated. Although it is well known that patients with PH1 have high levels of oxalate after liver-kidney transplantation, there have been no reported cases of livedo reticularis occurring in a patient after this procedure. It is possible that the patient had an extremely large store of oxalate that was mobilized post-transplant. Although she had a functioning kidney graft after transplant, the amount of mobilized oxalate could have been more than the transplant kidney could excrete. It is also possible that the kidney graft developed nephrocalcinosis, although a transplant kidney biopsy did not show evidence of this. In addition, she had no laboratory evidence of renal function abnormalities making the possibility of nephrocalcinosis unlikely. Her urine oxalate levels had been normalized with hemodialysis and although her oxalate load had been reduced by multiple plasmapheresis treatments, her cutaneous lesions persisted. Many factors could have contributed to recurrent systemic oxalosis and development of livedo reticularis.

The patient we describe with PH1, presented with livedo reticularis and ulcerations of her lower extremities 16-months after a combined renal-liver transplantation. To our knowledge, this is the thirteenth reported case of primary hyperoxaluria with cutaneous findings, and the first documented case of cutaneous manifestations of hyperoxaluria after transplantation in the literature.


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