Liver & intrahepatic bile ducts
Developmental anomalies / cysts
Navajo hepatopathy


Topic Completed: 12 August 2020

Minor changes: 12 August 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Navajo hepatopathy

Ryan Rebbe, M.D.
Joshua A. Hanson, M.D.
Page views in 2020 to date: 170
Cite this page: Rebbe R, Hanson JA. Navajo hepatopathy. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/livernavajohepatopathy.html. Accessed September 26th, 2020.
Definition / general
  • A rare hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome (MDS) with nonspecific clinical and pathologic features aside from Navajo ancestry (Acta Gastroenterol Belg 2016;79:463)
Essential features
  • mtDNA depletion syndrome caused by MPV17 missense mutation (Am J Hum Genet 2006;79:544)
  • Nonspecific cirrhotic findings in a patient with Navajo ancestry
  • Megamitochondria within hepatocytes
  • Mixed macrovesicular and microvesicular steatosis
Terminology
  • Navajo neurohepatopathy
  • MPV17 related hepatocerebral mitochondrial DNA depletion syndrome
ICD coding
  • ICD-10: K74.60 - liver cirrhosis NOS
Epidemiology
Sites
Pathophysiology
  • Autosomal recessive inheritance pattern (Am J Hum Genet 2006;79:544)
  • MPV17 encodes channel forming protein of inner mitochondrial membrane and is thought to be involved in deoxynucleotide homeostasis (Am J Hum Genet 2006;79:544)
  • Exact pathophysiology is still unclear (Am J Hum Genet 2006;79:544)
  • The mutation results in:
    • Depletion of mtDNA
    • Deformation of mitochondrial cristae (folds within inner membrane to increase surface area for electron transport chain to occur) (Hepatology 2001;34:776)
      • Creating megamitochondria
    • Decreased ATP causes cascade of effects:
      • Increased reliance on glycolysis for ATP production, leading to hypoglycemia and increased lactate production
      • Compensatory decrease in CO2
    • Affects sites most reliant on ATP; see Sites for more details
Etiology
Diagrams / tables

Images hosted on other servers:

Proteins involved in mtDNA replication

Clinical features
Diagnosis
Laboratory
Radiology description
Prognostic factors
  • Overall poor prognosis (Acta Gastroenterol Belg 2016;79:463)
  • Mortality rates (Hum Mutat 2018;39:461):
    • 66% die during infancy
    • 13% die in early childhood (1 - 5 years old)
    • 2% die in adolescence
    • 1% die in early adulthood
    • 18% reported alive in 2018 across all age groups
    • Oldest reported case at 25 years old
Case reports
Treatment
Microscopic (histologic) description
  • The following features are characteristic but not pathognomonic:
    • Mixed macrovesicular and microvesicular steatosis with hepatocanalicular cholestasis (J Pediatr 1999;135:482)
    • Ballooning hepatocellular degeneration indistinguishable from typical steatohepatitis
    • Red granular hepatocytes containing abnormal megamitochondria (Acta Gastroenterol Belg 2016;79:463)
    • Scattered acidophil bodies (Acta Gastroenterol Belg 2016;79:463)
    • Bridging fibrosis and cirrhosis with nonspecific portal / septal ductular reaction (J Pediatr 1999;135:482)
    • Juxtaposed cirrhotic nodules appear fatty and oncocytic due to variable accumulations of fat and megamitochondria
Microscopic (histologic) images

Contributed by Joshua A. Hanson, M.D.
Steatohepatitis

Steatohepatitis

Macrovesicular steatosis

Macrovesicular steatosis

Megamitochondria

Megamitochondria

Mixed steatosis and megamitochondria

Mixed steatosis and megamitochondria

Juxtaposed cirrhotic nodules

Juxtaposed cirrhotic nodules

Canalicular cholestasis

Canalicular cholestasis


Cirrhosis

Cirrhosis

Copper stain

Copper stain

Positive stains
Negative stains
Electron microscopy description
  • Enlarged pleomorphic mitochondria with dilated cristae
  • Lack of dense mitochondrial matrix granules
  • Numerous minute lipid droplets within hepatocytes (Hepatology 2007;46:1218)
Molecular / cytogenetics description
  • Autosomal recessive germline MPV17 missense mutation; gene is located on short arm of chromosome 2 (2p23.3)
  • Homozygous R50Q: glutamine (Q) replaces arginine (R) at position 50 on both alleles (Am J Hum Genet 2006;79:544)
    • Diagnosis is done by sequencing
    • There are 22 other reported missense mutations of MPV17 protein that cause similar pathology, i.e. R50W, P64R, etc. (Hum Mutat 2018;39:461)
    • Other mutations that cause mtDNA depletion syndrome:
Sample pathology report
  • Liver, biopsy:
    • Cirrhotic liver with steatohepatitis, hepatocanalicular cholestasis and intracytoplasmic megamitochondria (see comment)
    • Comment: A trichrome stain demonstrates an effaced nodular architecture with dense bands of bridging fibrosis (cirrhosis). There is mild portal / septal chronic inflammation consisting predominantly of lymphocytes with rare plasma cells. The inflammation is confined to the fibrous areas and the native bile ducts are not preferentially involved. There is no evidence of ductopenia. There is mixed macrovesicular and microvesicular steatosis with areas of ballooning hepatocellular degeneration indicative of steatohepatitis. There is canalicular and hepatocellular cholestasis. Acidophil bodies are seen and many hepatocytes contain course pink granules, consistent with megamitochondria. These findings in a pediatric patient with cirrhosis and Navajo ancestry would be compatible with Navajo neurohepatopathy in the proper clinical setting. This diagnosis would, however, need to be supported by additional testing (quantitative mtDNA analysis on fresh frozen tissue or genetic testing).
Differential diagnosis
Board review style question #1

    The finding highlighted by the image is discovered in a liver biopsy of a 2 year old male of Navajo ancestry with liver failure. What is the mutation associated with this disease?

  1. ATP7B
  2. C282Y
  3. MPV17
  4. TP53
Board review answer #1
C. MPV17

Comment Here

Reference: Navajo hepatopathy
Board review style question #2
    Which of the following ancillary studies supports a diagnosis of Wilson disease as opposed to Navajo hepatopathy?

  1. Markedly elevated liver copper concentration
  2. Positive copper immunohistochemistry
  3. Positive MPV17 germline testing
  4. Reduced hepatic mtDNA content
Board review answer #2
A. Markedly elevated liver copper concentration

Comment Here

Reference: Navajo hepatopathy
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