Liver and intrahepatic bile ducts - nontumor
Metabolic diseases
Primary hyperoxaluria



Editorial Board Member: Raul S. Gonzalez, M.D.
Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 1 May 2018

Revised: 23 January 2019, last major update May 2018

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PubMed Search: Primary hyperoxaluria[title] AND Liver AND (free full text[sb] AND Humans[Mesh])

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Cite this page: Lategan B. Primary hyperoxaluria. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/liverprimaryhyperox.html. Accessed February 18th, 2019.
Definition / general
  • Primary hyperoxaluria is a rare genetic disorder in which defective glyoxylate metabolism results in excessive oxalate production
  • Excess oxalate is deposited as insoluble calcium oxalate salts in the kidneys and systemically (systemic oxalosis), including in 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 (Curr Rheumatol Rep 2013;15:340, N Eng J Med 2013;369)
Essential features
  • Birefringent oxalate crystals are noted in vessel walls and connective tissues of the portal areas of explanted livers, the kidneys (Arch Pathol Lab Med 2002;126:1250) and other affected organs
  • Three most common subtypes are caused by mutations in the AGXT (type 1), GRHPR (type 2) and HOGA1 (type 3) genes
Epidemiology
Pathophysiology
  • Glyoxylate 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
  • Combination of direct renal tubular toxicity and obstruction results in renal injury with subsequent end stage renal failure in the more severe subtypes
  • Type 1 is typically the most severely affected of the 3 types (Kidney Int 2014;86:1197, Ann Clin Lab Sci 2013;43:328)
Diagrams / tables

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Diagnosis and treatment of primary hyperoxalurias

Clinical features
Diagnosis
  • Diagnosis is suspected on clinical (recurrent urolithiasis or nephrocalcinosis) and biochemical grounds and 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 type 1
  • Immunoblot assays allow analysis of the protein and immunoelectron examination illustrates the near absence of AGT in peroxisomes
    Laboratory
    • Markedly increased urinary oxalate excretion (> 1 mmol/1.73 m² per day [90 mg/1.73 m² per day])
    • As long as glomerular filtration rates are within normal limits, plasma oxalate concentration remains normal
    • Calcium oxalate renal and bladder stones
    Radiology images

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    Oxalate osteopathy

    Abdomen Xray and renal ultrasonography

    Systemic involvement ("oxalosis")

    Prognostic factors
    • Most type 1 and 2 patients require ongoing medical treatment
    • Type 3 becomes clinically silent by age 6 years and does not typically progress beyond mild renal impairment
    Case reports
    Treatment
    • 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 functionally normal
    • Combined liver and renal transplantation is often necessary due to end stage renal disease in types 1 and 2
    • 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)
    Gross images

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    Calcium oxalate stones

    Microscopic (histologic) description
    • Birefringent oxalate crystals in vessel walls and connective tissues of the portal areas of explanted livers and other affected organs (Arch Pathol Lab Med 2002;126:1250)
    Microscopic (histologic) images

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    Liver with portal birefringent oxalate crystals (case of the Week #436)

    Molecular / cytogenetics description
    • Type 1 demonstrates mutations in the AGXT gene, which encodes for the hepatic peroxismal enzyme alanine: glyoxylate aminotransferase (AGT)
    • Type 2 has defects in the GRHPR gene, which encodes for GRHPR enzyme
    • Type 3 demonstrates defects in the HOGA1 gene which encodes for the mitochondrial 4-hydroxy-2-oxoglutarate (HOG) aldolase enzyme
    • A small subset of patients (~5%) do not have demonstrable mutations in any of these three genes (N Engl J Med 2013;369, Int J Nephrol 2011;2011:864580)
    Molecular / cytogenetics images

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    GRHPR mutation

    Differential diagnosis
    Board review question #1
      The type of kidney and bladder stones most often encountered in primary hyperoxaluria are

    1. Calcium stones
    2. Mixed stones
    3. Pyruvate stones
    4. Struvite stones
    Board review answer #1
    A. Calcium stones. Oxalate excretion is almost entirely via the kidneys, predominantly as highly insoluble calcium salts.
    Board review question #2
      What is the most common genetic mutation and associated abnormal enzyme affecting 80% of patients with primary hyperoxaluria?

    1. AGXT gene and AGT enzyme
    2. GRHPR gene and GRHPR enzyme
    3. HOGA1 gene and HOG aldolase enzyme
    Board review answer #2
    A. AGXT gene and AGT (hepatic peroxismal enzyme alanine: glyoxylate aminotransferase)