Liver and intrahepatic bile ducts - nontumor
Metabolic diseases
Primary hyperoxaluria

Author: Belinda Lategan, M.D.

Revised: 15 May 2018, last major update May 2018

Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.

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

Cite this page: Lategan, B. Primary hyperoxaluria. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/liverprimaryhyperox.html. Accessed June 20th, 2018.
Definition / general
  • Primary hyperoxaluria (PH) is a rare genetic disorder in which defective glyoxalate 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 gene (type 1), GRHPR gene (type 2) and HOGA1 gene (type 3)
Pathophysiology
  • 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
  • Combination of direct renal tubular toxicity and obstruction results in renal injury with subsequent end stage renal failure in the more severe subtypes
  • 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)
  • 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)
Clinical features
  • 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 (Ann Clin Lab Sci 2013;43:328, Pediatr Nephrol 2015;30:1781)
  • Diagnosis
    • A diagnosis of primary hyperoxaluria suspected on clinical (recurrent urolithiasis or nephrocalcinosis) 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 AGTdeficiency in PH type 1
    • Immunoblot assays allow analysis of the protein and immunoelectron examination illustrates the near absence of AGT in peroxisomes
    • Algorithm for diagnosis and treatment
    Laboratory
    • Markedly increased urinary oxalate excretion (greater than 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
    • Birefringent oxalate crystals on biopsy (liver, kidney) in the presence of the appropriate clinical history (superseded by genetic testing) (Kidney Int 2009;75:1264)
    Radiology images

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    Oxalate osteopathy

    Abdomen Xray and renal ultrasonography

    Systemic involvement ("oxalosis")

    Prognostic factors
    • Most 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
    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 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)
    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

    Images hosted on PathOut server:

    Case of the Week #436



    Images hosted on other servers:

    Crystals in portal areas

    Calcium oxalate monohydrate crystals

    Extensive starburst crystal deposition in bone marrow

    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 PH?

    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: glyoxalate aminotransferase)
    Board review question #3
      True or false: Isolated renal transplantation is the treatment of choice for PH.

    Board review answer #3
    False. Renal transplantation without concomitant liver transplantation is associated with a higher rate of transplant failure due to recurrent oxalate induced renal injury