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13 September 2017 - Case of the Week #436

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Case of the Week #436

Clinical history:
A 30 year old woman with clinical end stage renal disease and end stage liver disease underwent a combined kidney/liver transplant. The microscopic images are from the liver explant.

Histopathology images:

What is your diagnosis?

Primary hyperoxaluria involving the liver

Test question (answer at the end):
The type of kidney and bladder stones most often encountered in primary hyperoxaluria (PH) are:

A. Pyruvate stones
B. Calcium stones
C. Struvite stones
D. Mixed stones

Primary hyperoxaluria (PH) is a rare genetic disorder with autosomal recessive inheritance. Glyoxalate metabolism, which almost exclusively occurs in hepatocytes, is defective and results in excessive oxalate production. Oxalate excretion is almost entirely via the kidneys, predominantly as highly insoluble calcium salts. Oversaturation of the renal tubular filtrate leads to crystallization in the renal tubules, nephrocalcinosis and urolithiasis, often with superimposed infection.

The combination of direct renal tubular toxicity and obstruction results in renal injury with subsequent end stage renal failure in the more severe subtypes. Calcium oxalate deposition in non-renal tissues (systemic oxalosis), including the retina (diminished visual acuity), myocardium (conduction defects), blood vessel walls (vascular occlusion and gangrene), skin (livedo reticularis, calcinosis cutis metastatica, gangrene), bone (pain, joint immobility, anemia, fractures) and central nervous system also occurs (Curr Rheumatol Rep 2013;15:340, N Eng J Med 2013;369).

The three most common subtypes of primary hyperoxaluria are caused by mutations in one of three genes. PH Type 1 affects 80% of patients and demonstrates mutations in the AGXT gene, which encodes for the hepatic peroxismal enzyme alanine: glyoxalate aminotransferase (AGT). The phenotype is heterogeneous, but typically patients with PH type 1 are the most severely affected of the three most common types. PH Type 2, which affects ~10% of patients, has defects in the GRHPR gene, which encodes for GRHPR enzyme. Patients tend to be less severely affected compared to type 1 PH. PH Type 3, ~5% of cases, demonstrates defects in the HOGA1 gene which encodes for the mitochondrial 4-hydroxy-2-oxoglutarate (HOG) aldolase enzyme. A small subset of patients (~5%) with primary hyperoxaluria does not have demonstrable mutations in the any of these three genes (N Engl J Med 2013;369, Int J Nephrol 2011;2011:864580).

Primary hyperoxaluria typically manifests in infancy or childhood with recurring kidney and bladder stones and other symptoms of systemic oxalosis, but some patients are only diagnosed in adulthood. The majority of type 1 and 2 PH patients require ongoing medical treatment. Type 3 PH becomes clinically silent by age 6 years and patients do not typically progress beyond mild renal impairment. In the most severely affected patients, liver transplantation is currently the only cure as this addresses the underlying causative enzyme deficiency, although the organ is otherwise normal. Combined liver and renal transplantation is often necessary due to end stage renal disease in types 1 and 2 PH. Renal transplantation without concomitant liver transplantation is associated with a higher rate of transplant failure due to recurrent oxalate induced renal injury (N Engl J Med 2013;369, Int J Nephrol 2011;2011:864580, Curr Rheumatol Rep 2013;15:340).

A diagnosis of primary hyperoxaluria suspected on clinical and biochemical grounds can be confirmed with genetic testing for the most common gene mutations (AGXT, GRHPR and HOGA1). Antenatal and preimplantation diagnosis is possible in affected families. Prior to the availability of genetic testing, liver biopsy was required to demonstrate AGT deficiency in PH type 1. Immunoblot assays allow analysis of the protein and immunoelectron examination illustrates the near absence of AGT in peroxisomes.

Findings in explanted livers, such as in this case, include birefringent oxalate crystals in vessel walls and connective tissues of the portal areas (Arch Pathol Lab Med 2002;126:1250). Oxalate crystals may also be seen in organs of patients with secondary hyperoxalosis, including enteric hyperoxaluria and ethylene glycol poisoning (Curr Rheumatol Rep 2013;15:340).

Test Question Answer:
Calcium stones. Oxalate excretion is almost entirely via the kidneys, predominantly as highly insoluble calcium salts.

Additional References:

Niaudet, P.: UpToDate, Primary hyperoxaluria, 2017

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