Difference between revisions of "Medical liver disease"

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===General===
===General===
*Associated with renal transplants, [[bone marrow transplant]]s and [[vasculitides]].<ref name=Ref_PBoD922>{{Ref PBoD|922}}</ref>
*Associated with renal transplants, [[bone marrow transplant]]s and [[vasculitides]].<ref name=Ref_PBoD922>{{Ref PBoD|922}}</ref>
*Can lead to [[portal hypertension]] and many of the associated complications.
*Can lead to [[portal hypertension]] and many of the associated complications.<ref name=pmid22554152>{{Cite journal  | last1 = Bissonnette | first1 = J. | last2 = Généreux | first2 = A. | last3 = Côté | first3 = J. | last4 = Nguyen | first4 = B. | last5 = Perreault | first5 = P. | last6 = Bouchard | first6 = L. | last7 = Pomier-Layrargues | first7 = G. | title = Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension. | journal = J Gastroenterol Hepatol | volume = 27 | issue = 8 | pages = 1336-40 | month = Aug | year = 2012 | doi = 10.1111/j.1440-1746.2012.07168.x | PMID = 22554152 }}
</ref>


====Etiology====
====Etiology====
*Arterial hypervascularity secondary to loss of hepatic vein radicles (loss of central venule in hepatic lobule).<ref>{{Ref PBoD|922}}</ref>
*Arterial hypervascularity secondary to loss of hepatic vein radicles (loss of central venule in hepatic lobule).<ref name=Ref_PBoD922>{{Ref PBoD|922}}</ref>


ASIDE: radicle = ramulus - smallest branch or vessel or nerve.<ref name=Dorlands2>Dorland's Medical Dictionary. 30th Ed.</ref>
ASIDE: radicle = ramulus - smallest branch or vessel or nerve.<ref name=Dorlands2>Dorland's Medical Dictionary. 30th Ed.</ref>

Revision as of 11:20, 24 April 2013

This article deals with medical liver disease. An introduction to the liver and approach is found in the liver article.

Every differential in liver pathology has "drugs"[1] -- if it isn't clearly malignancy.

Liver neoplasms are dealt with in the liver neoplasms article.

Viral hepatitis

These are common. The diagnoses are based on serology. The serology is covered in the viral hepatitis section in the liver pathology article.

Typically classified as:[2][3]

  1. Acute < 6 months duration.
  2. Chronic > 6 months duration.

Hepatitis A

  • Infection is self-limited, i.e. not persistent.
  • Usually asymptomatic in children.[4]
  • Serology is diagnostic.

Hepatitis B

Hepatitis B virus, abbreviated HBV, redirects here.

General

Associated pathology:

Microscopic

Features:

  • Lobular inflammation - this is non-specific finding.
    • Hepatocyte necrosis:
      • Necrotic hepatocytes look a lot like neutrophils - however:
        • Cytoplasm is more pink.
        • Round apoptotic bodies.
  • Ground glass hepatocytes - see liver pathology article.

Image: GGH - high mag. (WC).

DDx:

IHC

Hepatitis C

General

  • Leads to hepatocellular carcinoma in the setting of cirrhosis.
  • Tends to be chronic; the "C" in "hepatitis C" stands for chronic.
  • Diagnosis is by serology.

Associated pathology:

Microscopic

Features:

  • Lobular inflammation - this is non-specific finding.
    • Usually Grade 1, rarely Grade 2 and almost never Grade 3 or Grade 4.[5]
  • Periportal steatosis in genotype 3.[6]
    • Steatosis in hepatitis C is usually a secondary pathology, i.e. a separate pathologic process.[7]

DDx:

Other infections

  • Hydatid disease (Hydatid cyst).
  • Ascaris.
  • Fasciola

Hydatid disease

  • AKA hydatid cyst.

General

Microscopic

Features:

Images:

Metabolic and toxic

Alcoholic liver disease

General

  • Acute and/or chronic liver changes due to excessive alcohol use - includes:
    • Alcoholic steatohepatitis (ASH), AKA alcoholic hepatitis.[9]
      • Alcoholic hepatitis can be with minimal steatosis.[10]
    • Steatosis - classically macrovescicular and centrilobular.
    • Alcoholic cirrhosis.

Classic lab findings in EtOH abusers

  • AST & ALT elevated with AST:ALT=2:1.
  • GGT elevated.
  • MCV increased.

Gross pathology/radiologic findings

  • Classically micronodular pattern.
    • May be macronodular.

Microscopic

See:

Features:

  • Often zone III damage.
  • Cholestatsis common, i.e. yellow staining.
    • NASH (non-alcoholic steatohepatitis) usu. does not have cholestasis.[11]
  • Fibrosis starts at central veins.
  • Neutrophils (often helpful) -- few other things have PMNs. (???)
    • Neutrophils cluster around cells with Mallory hyaline.

Notes:

  • If portal inflammatory infiltrates more than mild, r/o other causes i.e. viral hepatitis.
  • Mallory bodies once thought to be characteristic; now considered non-specific and generally poorly understood.[12]
  • Some consider alcoholic liver disease a clinical diagnosis, i.e. as a pathologist one does not diagnose it.[13]

Non-alcoholic fatty liver disease

  • Abbreviated NAFLD.
  • Fatty liver that is not due to alcohol; includes obesity-related fatty liver, metabolic disease/diabetes-related fatty liver.

NASH

  • Non-alcoholic steatohepatitis - see steatohepatitis section.
  • Histologically indistinguishable from ASH.
  • NASH is a clinical diagnosis based on exclusion of alcohol.

Steatohepatitis

General

  • Steatohepatitis is a label for a set of histopathologic findings.
  • Fat accumulation in hepatocytes.
    • It may be a pattern seen in drug toxicity, e.g. methotrexate toxicity.[14]

Etiology:

  1. Alcohol = alcoholic steatohepatitis (ASH).
  2. Not alcohol = non-alcoholic steatohepatitis (NASH).
  3. Drug/toxin.[15]

Notes:

  • Pathologists can comment on the etiology; however, the histomorphology is not distinctive. In other words, ASH and NASH are clinical diagnoses.
  • Steatohepatitis is a misnomer. It is not an -itis; inflammation is not the (predominant) pathologic process.

Microscopic

Features:

  • Steatosis (usually macrovesicular) - key feature.
    • If less than 10% ... consider alt. diagnosis/disease process.
  • Hepatocyte injury:
    • Ballooning degeneration - key feature (see introduction to liver).
    • Mallory bodies.
      • Mallory body wannabes: "occasional cytoplasmic clumping".
  • +/-Chicken-wire perisinusoidal fibrosis +/- zone III (centrilobular) fibrosis (early).
    • Late-stage disease - portal bridging.[16]

Image: Steatohepatitis (WC).

DDx:

Grading steatohepatitis

Grading inflammation:[17]

  • Grade 1 - steatosis, occasional ballooning degeneration, PMNs.
  • Grade 2 - obvious ballooning, obvious PMNs, chronic inflammation.
  • Grade 3 - panacinar steatosis.

Autoimmune

Autoimmune hepatitis

  • Abbreviated AIH.

General

  • Several criteria exist to diagnose and histology (alone) is not sufficient.

Diagnosis

Simplifed diagnostic criteria (2008):[18]

  1. Antibody titer.
  2. Elevated IgG.
  3. Liver pathology.
  4. Exclusion of viral hepatitis.

Details (scoring):[18]

Finding Score
ANA or SMA 1:40 1 point
ANA or SMA 1:80 2 points
LKM-1 1:40 2 points
IgG upper normal 1 point
IgG 1.1x upper limit 2 points
Histology compatible 1 point
Typical AIH histo. 2 points
No viral hepatsis 2 points

Interpretation: Definite >= 7 points. Probable = 6 points.

Notes:

  • Autoantibodies may be seen in HCV.[18]
  • A normal IgG is very unusual in AIH - but may be seen in atypical variants with zone III involvment.

Abbreviations:

  • ANA = anti-nuclear antibody.
  • SMA = smooth muscle antibody.
  • LKM-1 = liver kidney microsomal type 1 antibody.

Microscopic

Classification:[18]

  • Typical:
    • Interface hepatitis (zone 1).
      • Lymphoplasmacytic infiltration of portal tracts / lobule.
    • Emperipolesis - one cell penetrates into another one (uncommon finding).
    • Hepatic rosette - inflammatory cells around reactive hepatocytes.[20]
  • Compatible:
    • Chronic hepatitis - lymphocytic dominant.
  • Atypical:
    • Signs of an other disease.

Notes:

  • PAS stain may be useful - find plasma cells.[21]
    • Lots of plasma cells should prompt consideration of AIH.
  • Atypical Autoimmune hepatitis may have zone III involvment (lymphoplasmacytic infiltrate)[22] and a normal IgG.[23]

Images:

Treatment

  • Immunosuppresants (prednisone, azathioprine).[22]

Primary biliary cirrhosis

  • Abbreviated PBC.

General

Epidemiology:

Etiology:

  • Autoimmune.

Serology:

Classic presentation:

  • Pruritis.

Pathophysiology:

  • Septal bile duct attacked.

Treatment:

  • Ursodeoxycholic acid.
  • May be indication for transplant.

Microscopic

Features:

  • "Florid duct lesion":[26]
    • Intraepithelial lymphocytes - in bile duct - key feature.
    • Bile duct epithelial cells with eosinophilic cytoplasm.[27]
  • Plasma cells.
  • Granulomas - close to bile duct.
    • Seen in classic presentation -- often not present or poorly formed.
  • Focal damage (may be missed on biopsy -- due to sampling).
  • "Garland" cirrhosis -- has irregular border (unlike in EtOH).
    • Garland originally "wreath of flowers" (in French).[28]

DDx:[29]

Notes:

  • PAS stain useful for examining basement membrane... which is lost in PBC.
  • Lobular inflammation should be minimal.

Images:

Staging PBC

PBC is staged according to Ludwig:[31]

  • Stage 1: Portal - inflammation or bile duct abnormalities.
  • Stage 2: Periportal - periportal fibrosis (enlargement of portal tracts) +/- inflammation.
  • Stage 3: Septal - septal fibrosis +/-inflammation in septa.
  • Stage 4: Cirrhosis - nodules of hepatocytes +/- inflammation.

Notes:

  • There can be significant variation in staging on biopsy - due to variability of fibrosis in a PBC liver.[32]
    • "Worst area" in biopsy specimen is used to determine stage.

Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome

  • Abbreviation AIH-PBC OS.

General

Epidemiology:

  • Rare.

Serology:[33]

  • AMA +ve.
  • Anti-dsDNA +ve.

Microscopic

See: autoimmune hepatitis and primary biliary cirrhosis.

Primary sclerosing cholangitis

  • Abbreviated PSC.
  • AKA pericholangitis; considered a synonym for small duct PSC.[34]

General

Serology:

  • p-ANCA (MPO-ANCA) +ve in ~ 90% of cases.[37]

Diagnosis

  • Diagnosed radiologically.
  • Liver biopsy is rarely useful diagnostically[38] - as the disease may be patchy.
    • The utility of the biopsy is staging.

Treatment

  • None very good.
  • May be indication for transplant.

Microscopic

Features:

  • Classic: "onion-skinning" - cells layer around the bile ducts; "onion skin" present in approx. 40% of cases.[39]
    • Not pathognomonic for PSC[39] - but not too much else looks like this on microscopy (ergo good fellowship exam question).
  • +/-Ductopenia.
  • +/-Ductal proliferation.

DDx:

  • Big.

Images:

Notes:

  • PSC often has minimal inflammation.[42]

Staging

Features:[43]

  • Stage I - focal portal inflammation, +/- duct abnormalities, no fibrosis.
  • Stage II - portal enlargement (fibrosis), +/- inflammation.
  • Stage III - bridging fibrosis + necrosis.
  • Stage IV - cirrhosis.

Notes:

  • Similar to PBC staging.

Hereditary

Caroli disease

General

Clinical:[46]

Note:

  • Caroli syndrome = Caroli disease + congenital hepatic fibrosis.[49]

Gross

  • Dilated bile ducts.[44]

Microscopic

Features:[46]

  • Dilated bile ducts.
  • Periductal fibrosis. (???)
  • +/-Fibrosis.

Image:

Hereditary hemochromatosis

For secondary causes see secondary hemochromatosis.

General

Epidemiology:

  • Genetic defect - HFE gene.[51]
    • One mutation (C282Y mutation) in up to 12.5% of people in populations of northern and central European origin.[52]
  • Onset in males earlier than females (due to menses).
  • Mutation thought to confer survival advantage - several theories (increased resistance to TB, S. typhi vs. decreased iron deficiency/increased iron absorption).[52]

Associated pathology (mnemonic: hemochromatosis can cause deposits anywhere):[53][54]

Pathophysiology:

Microscopic

Features:

  • Periportal iron deposition (early).
    • Late stage disease has diffuse iron deposition.
  • Brown granular - may vaguely look like lipofuscin on H&E.

Notes:

  • Iron in the bile ducts and endothelium used to be though specific of hereditary hemochromatosis.[57]
    • It is now thought to just reflect the severity of iron deposition, i.e. if the bile ducts and endothelium have iron - it is severe.

DDx - secondary hemochromatosis:

Images:

Stains

Iron stain +ve -- important.

  • Light blue haze is not enough.
    • Must be separated from siderosis -- iron in Kupffer cells.

Molecular

Wilson disease

General

Epidemiology:

  • Rare autosomal recessive - mutation in copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B).[58][59]
    • Heterozygote carrier rate approximately 1/100 persons.[58]
  • Young individuals - usually 12-23 years old.

Clinical:

  • Kayser-Fleischer rings --> on slit-lamp examination (green eyes).
  • May present to psychiatry or appear to be abusing EtOH.
  • Serum ceruloplasmin - lower than normal.

Etiology:

  • Excess copper -- due to genetic defect.

Microscopic

Features:

  • Nothing specific - known as the great mimicker of live pathology.
  • Steatosis.
  • Portal fibrosis.

Stains

  • Copper staining positive - only 15% of cases.
    • Other stains: rhodinine (red/orange granules = positive), orecin.

Notes:

  • Copper staining is a non-specific finding seen in many liver diseases; it is associated with impaired bile secretion.[60]

Additional testing

  • Mass spectrometry - determine portion of copper.

Alpha-1 antitrypsin deficiency

  • AKA alpha1-antiprotease inhibitor deficiency.

General

Etiology:

  • Genetic defect.
    • Prevalence 1 in 2000-5000.[61]

Causes:

  • Lung and liver injury.

Microscopic

Features:

  • Pink globules in zone 1 (periportal).
    • Globules not seen in children.
    • May not be present in late stage (cirrhotic).
    • Best seen on PASD stain.
    • Can be seen on H&E -- if one looks carefully.

Note:

  • The pink globules may be seen in the context of cirrhosis; cases should be confirmation with IHC.

Images:

Stains

IHC

  • A1-AT +ve globules.[63]

Other

Budd-Chiari syndrome

  • AKA hepatic vein obstruction.

General

  • Hepatic outflow obstruction.

Clinical triad:[64]

  • Ascites.
  • Abdominal pain.
  • Hepatomegaly.

Etiology:

Clinical DDx:

Microscopic

Features:[66]

  • Sinusoidal dilation in zone III (congestion).
  • +/-Hepatocyte drop-out.
  • +/-Centrilobular fibrosis.

DDx congestion:

Vanishing bile duct syndrome

General

  • Fatal.

DDx:[68]

Microscopic

Features:[68]

  • Loss of intrahepatitic bile ducts - key feature.
  • Cholestasis.

Note:

  • May occur without fibrosis and inflammation; thus, can be easy to miss.

IHC

  • CK7 -ve.
    • Marks bile ducts.

Congestive hepatopathy

General

  • Liver failure due to (right) heart failure.
  • AKA cardiac cirrhosis - a term used by clinicians.
    • Generally, it does not satisfy pathologic criteria for cirrhosis.[71]

Gross

  • "Nutmeg" liver - yellow spotted appearance.

Microscopic

Features:[72]

  • Zone III atrophy.
  • Portal venule (central vein) distension.
  • Perisinusoidal fibrosis - progresses to centrilobular fibrosis and then diffuse fibrosis.
  • Dilation of sinusoids in all zone III areas - key feature.[73]

Image: Congestive hepatopathy (WC).

Drug-induced liver disease

  • AKA drug-induced liver toxicity.

General

  • Drugs can do almost anything; may include: granulomata, bile duct loss, cholestasis, ischemic type injury.
  • Effects can be delayed -- temporal relationship not always obvious.

Microscopic

Features:

Images:

Specific patterns

Acute hepatits:

  • Related to Rx - most often antibiotics.

Steatohepatitis/steatosis:[75]

  • Amiodarone - cardiac arrhythmias.
  • Tamoxifen - breast cancer.
  • Carbamazepine - seizures.

Specific drugs

Acetaminophen:

  • Zone 3 necrosis.
    • Tx: N-acetylcysteine (NAC).[76]
      • NAC is an endogenous precursor to glutathione.[77]
    • Hepatotoxicity from N-acetyl-p-benzoquinoneimine (NAPQI) due to depletion of glutathione.[76]

Methotrexate - chronic use:

  • Histology:[78]
    • Features of steatohepatitis.
      • Zone III steatosis.
      • Ballooning degeneration.
    • Portal inflammation with mixed population (lymphocytes, macrophages, PMNs).
    • Nuclear atypia (hyperchromasia, pleomorphism, vacuolation).
      • Described as just nuclear size variation by some.[79]

Focal nodular hyperplasia

  • Abbreviated FNH.

General

Note:

  • Oral contraceptive pill (OCP) use does not appear to be a factor in the growth of these lesions;[82] however, the study claims there is nothing on hepatocellular adenomas -- yet I found a JAMA paper by Rooks et al.[83] on this topic.

Imaging

  • FNH enhances on the arterial phase in triphasic imaging, i.e. triphasic CT or MRI.[84][80]

Gross

Features:[85]

  • Well circumscribed, but no capsule.
  • Lighter than surrounding parenchyma, may be yellow.
  • +/-Stellate central scar with thick vessels.
    • Can be identified on medial imaging.

Note: Usually a solitary lesion.[84]

Microscopic

Features:[85]

  • Classically a stellate scar that has large arteries with fibromuscular hyperplasia.
    • Thin fibrous septa radiate from the central scar - surrounded by lymphocytes & bile ductules.
      • Normal hepatocytes between fibrous septae.

Practical features:

  1. Thick walled blood vessels.
    • Bile duct of same size not seen.
  2. Bile ductular proliferation at the edge of the fibrosis tissue.
  3. Clinical history: it is a focal lesion.

DDx:

  • Hepatic adenoma - may be difficult to distinguish, if no scar and no ductal proliferation.[86]
  • Cirrhosis - complete nodules
    • FNH has incomplete nodules.

Memory device FNH = focal lesion, numerous bile ductules, hyperplasia of arteries.

Images:

Nodular regenerative hyperplasia

General

Etiology

  • Arterial hypervascularity secondary to loss of hepatic vein radicles (loss of central venule in hepatic lobule).[85]

ASIDE: radicle = ramulus - smallest branch or vessel or nerve.[88]

Gross

  • Diffuse nodularity - whole liver.

Microscopic

Features:[85]

  • "Plump" hepatocytes surrounded by atrophic ones.
  • No fibrosis.

Sinuosoidal obstruction syndrome

  • May be referred to as Hepatic veno-occlusive disease.[89]

General

  • Term for obstruction due to toxicity from a chemotherapeutic agent.[90][66]

Clinical DDx:

Microscopic

Features:[66]

  • Subendothelial swelling in hepatic venules.

Negatives:

  • No thrombosis.

Polycystic kidney disease and the liver

General

Complications of PKD in the liver:[91]

  1. Infected cyst.
  2. Cholangiocarcinoma.
  3. Cholestasis/obstruction due to duct compression.[92]

Cysts:

  • Cysts in the liver, like the kidney, are thought to enlarge with age.

Microscopic

Features:[93]

  • Von Meyenburg complexes (bile duct hamartoma):
    • Cluster of dilated ducts with "altered" bile.
    • Surrounded by collagenous stroma.
    • Separate from the portal areas.[94]

Images:

Notes:

  • Appearance on ultrasound[95] and CT (hypodense)[96] - similar to metastases.

Peliosis hepatis

General

  • Associated with:
    • Infections.
    • Malignancy.
    • Other stuff.
  • Rarely biopsied.

Microscopic

Features:

  • Cyst lined by endothelium.
    • Usu. incomplete.
  • Blood.

Total parenteral nutrition

  • Abbreviated TPN.

General

  • Indication: short gut syndrome, others.

Microscopic

Variable - may range from: steatosis, steatohepatitis, cholestasis, fibrosis and cirrhosis.[97]

Features (classic):[98][99]

  • Steatosis (periportal) - early.
  • Cholestasis - late.

Giant cell hepatitis

  • AKA neonatal giant cell hepatitis.
See: Giant cell hepatitis.

Hepatic amyloidosis

  • AKA liver amyloidosis.
  • AKA amyloidosis of the liver.

General

  • Diffuse abundant amyloid within the space of Disse is associated with portal hypertension.[100]

Microscopic

Features:

  • Amorphous extracellular pink stuff on H&E - see amyloid article.

DDx:

Images:

Stains

Fulminant hepatic necrosis

General

Etiology:

Microscopic

Features:

  • Hepatocyte necrosis.
  • Bile duct proliferation.

DDx:

Secondary hemochromatosis

For the hereditary one see hereditary hemochromatosis.

General

  • Iron overload secondary to blood transfusions for hereditary or acquired anemia.[101]
  • Imaging considered the best test, as iron deposition is patchy.[101]

Selected hereditary causes:[101]

Selected acquired causes:[101]

Microscopic

See hereditary hemochromatosis.

See also

References

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  2. "Terminology of chronic hepatitis, hepatic allograft rejection, and nodular lesions of the liver: summary of recommendations developed by an international working party, supported by the World Congresses of Gastroenterology, Los Angeles, 1994.". Am J Gastroenterol 89 (8 Suppl): S177-81. Aug 1994. PMID 8048409.
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  7. OA. September 2009.
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  11. STC. 6 December 2010.
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