Medical liver disease

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

Micrograph showing ground glass hepatocytes, as seen in chronic hepatitis B. H&E stain.

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

Liver neoplasms are dealt with in the liver neoplasms article.

Medical liver biopsies are often non-specific, as the liver has the same appearance for many mechanisms of injury, especially when the injury is marked. The clinical history, serology and imaging are essential for proper interpretations in this domain of pathology.

Review of liver blood work

Inflammation activity

  • ALT.
  • AST.

Cholestatic markers

  • ALP.
  • GGT - used to assess whether the ALP is an "honest" value, elevated in cirrhosis.

Cirrhosis/decompensation

  • PLT - low is suggestive of dysfunction.
  • INR - high is bad, unless anticoagulated.

Other

  • Bilirubin.
    • Direct (AKA conjugated).
    • Indirect (AKA unconjugated).

A short DDx of elevated:[2]

  • Indirect:
    • Gilbert syndrome.
    • Crigler-Najjar syndrome type 1.
    • Crigler-Najjar syndrome type 2.
  • Direct:
    • Rotor syndrome.
    • Dubin-Johnson syndomre.

Viral hepatitis

  • HBV DNA.
  • HCV RNA.
  • HBs Ag, HBs Ab, HBe Ag, HBe Ab.
  • HCV Ab.

Others:

Hepatitis B

Meaning & utility of the various Hepatitis B tests:[3][4]

Test name Location Positive test Negative test Usual question
HBs Ag Surface Virus active No active infection Active infection?
HBs Ab Surface Exposed OR vaccinated No exposure OR no vaccine OR loss of Ab Immunization status?
HBe Ag Virus core Infect. w/ viral replication No active infection Active infect. w/ viral replication?
HBe Ab Virus core Exposed to virus Infect. w/o antibody response OR not exposed Immune response to infection?
HBV DNA - Active Not active/no exposure Viral load/how active?
HBc Ab Virus core Virus active/previous exposure No exposure Early active infection?

Notes:

  • HBc Ab may test for acute (IgM) or chronic infection - dependent on specific antibody test; it is often used to look for early infection.[4]
  • Carriers of hepatitis B: HBs Ag +ve, HBs Ab -ve, HBc Ag -ve, HBc Ab +ve, HBe Ag -ve, HBe Ab +ve.[5]

Markers for rare liver diseases

  • Ceruloplasm - low think Wilson's disease; typical value for Wilson's ~ 0.12 g/L.
    • <0.20 g/L is a criteria for Wilson's disease.[6]
  • Alpha-1 antitrypsin - if low think deficiency.

Hemosiderosis

  • Ferritin - high.
  • Iron saturation - high.

Causes:

  • Hemochromatosis.
  • Hemolysis, chronic.
  • Cirrhosis.

Medical imaging

Blood flow:[7]

  • Hepatopedal flow = normal portal vein flow.
  • Hepatofugal flow = reversed portal vein flow.

Interventional measurements

Wedged to free hepatic venous pressure:[8]

Liver biopsy

Medical liver biopsy adequacy

Liver biopsy specimens should be:[9]

  • 2.0 cm in length and contain 11-15 portal tracts,
  • The core should be deeper than 1.0 cm from the liver capsule; specimens close to the capsule may lead to over grading of fibrosis.

Reporting

Specimen, procedure:
- Diagnosis.

The diagnosis usually contains grading and staging information, e.g. activity 2 /4, Laennec fibrosis stage 1 /4.

In the context of medical liver disease:

  • Grade = inflammation/activity.
  • Stage = severity of fibrosis/architectural changes.

Notes:

  • The term "acute" is infrequently used in liver pathology.
  • In the liver: neutrophils is not acute -- unlike most elsewhere in the body.[10]

A microscopic checklist

Size of biopsy: Adequate
Fragmentation: Absent
Fibrosis: Stage 2-3/4, mostly stage 2
Fibrous septa: Present
Septa with curved contours: Present – focally only
Large droplet steatosis (% of hepatocytes): Present, moderate 60%
Ballooning of hepatocytes: Present, rare
Mallory-Denk bodies: Present, rare
Portal inflammation: Present
Interface activity: Minimal (0-1/4)
Lobular necroinflammation: Minimal
Ducts: Present in normal numbers
Duct injury: Absent
Ductular reaction: Absent
Cholestasis: Absent
Terminal hepatic venules: Present
Iron stain: Absent
Ground glass cells with routine stains: Absent
PASD for alpha-1 antitrypsin droplets: Negative 

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:[11][12]

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

Hepatitis A

  • Infection is self-limited, i.e. not persistent.
  • Usually asymptomatic in children.[13]
  • 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.

DDx:

Image

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.[15]
  • Periportal steatosis in genotype 3.[16]
    • Steatosis in hepatitis C is usually a secondary pathology, i.e. a separate pathologic process.[17]

DDx:

Other infections

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

Hydatid disease

  • AKA hydatid cyst.

General

Microscopic

Features:

Images

www:

Metabolic and toxic

Alcoholic liver disease

General

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.[21]
  • 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.[22]
  • Some consider alcoholic liver disease a clinical diagnosis, i.e. as a pathologist one does not diagnose it.[23]

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

Autoimmune

Autoimmune hepatitis

  • Abbreviated AIH.

Primary biliary cirrhosis

  • Abbreviated PBC.

Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome

  • Abbreviation AIH-PBC OS.

General

Epidemiology:

  • Rare.

Serology:[24]

  • AMA +ve.
  • Anti-dsDNA +ve.

Microscopic

See: autoimmune hepatitis and primary biliary cirrhosis.

Primary sclerosing cholangitis

  • Abbreviated PSC.

Hereditary

Caroli disease

General

Clinical:[27]

Note:

  • Caroli syndrome = Caroli disease + congenital hepatic fibrosis.[30]

Gross

  • Dilated bile ducts.[25]

Microscopic

Features:[27]

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

Image:

Hereditary hemochromatosis

For secondary causes see secondary hemochromatosis.

Wilson disease

Alpha-1 antitrypsin deficiency

  • AKA alpha1-antiprotease inhibitor deficiency.

Other

Budd-Chiari syndrome

  • AKA hepatic vein obstruction.

General

  • Hepatic outflow obstruction.

Clinical triad:[32]

  • Ascites.
  • Abdominal pain.
  • Hepatomegaly.

Etiology:

Clinical DDx:

Microscopic

Features:[34]

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

DDx congestion:

Vanishing bile duct syndrome

General

  • Fatal.

DDx:[36]

Microscopic

Features:[36]

  • 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.[39]

Gross

  • "Nutmeg" liver - yellow spotted appearance.

Microscopic

Features:[40]

  • 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.[41]

DDx:

Images

Drug-induced liver disease

  • AKA drug-induced liver toxicity.

Focal nodular hyperplasia

  • Abbreviated FNH.

Nodular regenerative hyperplasia

General

Etiology

  • Arterial hypervascularity secondary to loss of hepatic vein radicles (loss of central venule in hepatic lobule).[42]

ASIDE: radicle = ramulus - smallest branch or vessel or nerve.[44]

Gross

  • Diffuse nodularity - whole liver.

Microscopic

Features:[42]

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

Sinuosoidal obstruction syndrome

  • May be referred to as Hepatic veno-occlusive disease.[45]

General

  • Term for obstruction due to toxicity from a chemotherapeutic agent.[46][34]

Clinical DDx:

Microscopic

Features:[34]

  • Subendothelial swelling in hepatic venules.

Negatives:

  • No thrombosis.

Polycystic kidney disease and the liver

General

Complications of PKD in the liver:[47]

  1. Infected cyst.
  2. Cholangiocarcinoma.
  3. Cholestasis/obstruction due to duct compression.[48]

Cysts:

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

Microscopic

Features:[49]

  • Von Meyenburg complexes (bile duct hamartoma):
    • Cluster of dilated ducts with "altered" bile.
    • Surrounded by collagenous stroma.
    • Separate from the portal areas.[50]

Images:

Notes:

  • Appearance on ultrasound[51] and CT (hypodense)[52] - 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.[53]

Features (classic):[54][55]

  • 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

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.[56]
  • Imaging considered the best test, as iron deposition is patchy.[56]

Selected hereditary causes:[56]

Selected acquired causes:[56]

Microscopic

See hereditary hemochromatosis.

See also

References

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