Medical liver disease

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

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" -- 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:

• 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:

• Epstein-Barr virus (EBV).
• Cytomegalovirus (CMV) - especially in the immune incompetent.

Hepatitis B

Meaning & utility of the various Hepatitis B tests:

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.
• Carriers of hepatitis B: HBs Ag +ve, HBs Ab -ve, HBc Ag -ve, HBc Ab +ve, HBe Ag -ve, HBe Ab +ve.

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.
• Alpha-1 antitrypsin - if low think deficiency.

Hemosiderosis

• Ferritin - high.
• Iron saturation - high.

Causes:

• Hemochromatosis.
• Hemolysis, chronic.
• Cirrhosis.

Medical imaging

Blood flow:

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

Interventional measurements

Wedged to free hepatic venous pressure:

• Normal = 1-4 mmHg.
  • Elevated in portal hypertension.

Liver biopsy

Medical liver biopsy adequacy

Liver biopsy specimens should be:

• 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

Main article: Pathology reports

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.

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:

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

Hepatitis A

• Infection is self-limited, i.e. not persistent.
  • May present as fulminant hepatic necrosis.
• Usually asymptomatic in children.
• Serology is diagnostic.

Hepatitis B

Hepatitis B virus, abbreviated HBV, redirects here.

Main article: Hepatitis B

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:

• Membranoproliferative glomerulonephritis.
• Membranous nephropathy.
• Cryoglobulinemia.

Microscopic

Features:

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

Images

Hepatitis C case for Libre Pathology	Metavir activity index 1 (Piecemeal necrosis 0-1, Lobular necrosis 1), Metavir fibrosis stage 2. Hepatitis C genotype 1a. Expanded, dark triads (UL blue arrowhead). Focus of spotty necrosis (UR green arrowhead). Reticulin shows occasional, equivocal foci of piecemeal necrosis, with a thin black line possibly encircling a hepatocytes (LL yellow arrowhead); the activity index is unaffected by the difference in piecemeal necrosis score. Trichrome shows portal fibrosis with extension outside area of blood vessels (LR purple arrowhead) Original oculars UL 2X, UR 20X, LL 40X, LR 40X
Hepatits C case for Libre Pathology	Metavir activity index 2 (Piecemeal necrosis 2, Lobular necrosis 1). Hepatitis C genotype 3a. Steatosis, not pan-acinar and dark, expanded triads(UL) with the inset showing a Councilman body. Reticulin collapse, not portal-central (UR green arrowhead). Reticulin with more than focal piecemeal necrosis in some triads/tracts (LL magenta arrowheads) Trichrome stain of a tract (the entire structure may be a large bridge) with thinner bridges (LR cyan arrowheads). Original oculars. UL 4X (inset 40X with higher magnification), UR 20X, LL 40X, LR 10X
Metavir stage 4 fibrosis in patient with HCV, for Libre Pathology	Metavir activity index 3 (Piecemeal necrosis 2, Lobular necrosis 2), Metavir fibrosis stage 4. Hepatitis C genotype 1a. Inflamed bands separate hepatocyte regions distorted by steatosis (UL). Bordering tract and acini (UR) lymphocytes, macrophages, eosinophils, and rare neutrophils (black arrowhead) invest both proliferated bile ducts (yellow arrowheads) and hepatocytes, some showing ballooning degeneration (green arrowhead). Reticulin shows hepatocyte cords often two nuclei thick bounded by directionless sinusoids, consistent with a regenerative nodule (LL). Trichrome shows extensive bridging with a potential flattened nodule; although a debate about the presence or absence of definite fibrosis would have existed, with the Metavir scoring system, this is considered fibrosis stage 4 (LR). Original oculars UL 4X, UR 40X, LL 20X, LR 10X

DDx:

• Hepatitis B (without ground glass hepatocytes).
• Autoimmune hepatitis.
• Primary biliary cirrhosis without granulomas.
• Drug reaction.

Other infections

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

Hydatid disease

• AKA hydatid cyst.

General

• Etiology: Echinococcus.

Microscopic

Features:

• Laminated wall +/- calcification.
• Organisms -- see Echinococcus.

Images

• 

  Liver cyst wall - intermed. mag. (WC)

• 

  Liver cyst wall - high mag. (WC)

• 

  Characteristic laminated portion - intermed. mag. (WC)

• 

  Characteristic laminated portion - high mag. (WC)

www:

• Hydatid cyst (med.sc.edu).
• Hydatid cyst (atlas.or.kr).
• Hydatid cyst (casereports.bmj.com).

Abscess

Abscess. A process replaces most of the liver parenchyma (UL 20X). Fibrinopurulent exudate apposes granulation tissue (UR 200X). Neutrophils lie in widened sinusoids (LL 200X).Trichrome shows collagenization of spaces of Disse. Scarring about an abscess or other mass lesion should not be interpreted as reflective of the liver in general (LR 200X).

Coccidiomycosis

Coccidiomycosis Table show GRAN-COC

Note the granulomas in otherwise undisturbed liver (UL), the larger prior granuloma with centrally crowded cells & lady slipper macrophage nuclei (UR), the center of the granuloma with pyknotic macrophage nuclei "necrotizing" (LL), and the organisms on GMS stain (LR).

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.
    • Alcoholic hepatitis can be with minimal steatosis.
  • 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:

• Steatohepatitis section and ballooning degeneration section.

Features:

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

Images

Cirrhosis in a patient with a history of alcohol abuse

Cirrhosis in a person with alcohol abuse. At low power bands separate hepatocyte regions (UL). Higher power at left shows isles of hepatocytes, some ballooned; at right, hepatocytes with many lumens, at lower power perhaps suggesting steatosis, here evidencing regeneration (UL). Focus of spotty necrosis (UR). PAS-D stain showing extensive benign bile duct proliferation, overall localized, with red rimd (LL). Trichrome shows fibrosis about nodules (LR). Original oculars UL 4X, UR 20X, LL 40X, LR 10X

Alcoholic hepatitis without cirrhosis. No history of viral disease. AMA negative. Expanded, inflamed triads with increased bile duct/vascular openings. Mild steatosis (UL 40X). Trichrome stain shows periportal fibrosis [red arrowheads] (UR 200X). PAS with diastase stain shows proliferated bile ductules [blue arrowheads] in stroma with mixed inflammatory infiltrate (LL 400X) Neutrophils about ballooned hepatocyte (satellitosis) [yellow arrowheads]. Councilman bodies [green arrowheads] (LR 400X).

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

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

Main article: Steatohepatitis

Autoimmune

Autoimmune hepatitis

• Abbreviated AIH.

Main article: Autoimmune hepatitis

Primary biliary cirrhosis

• Abbreviated PBC.

Main article: Primary biliary cirrhosis

Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome

• Abbreviation AIH-PBC OS.

General

Epidemiology:

• Rare.

Serology:

• AMA +ve.
• Anti-dsDNA +ve.

Microscopic

See: autoimmune hepatitis and primary biliary cirrhosis.

AIH/PBC overlap. AMA & ANA positive with Alkaline phosphatase > 2 upper limit of normal & one ALT > 5 times upper limit of normal. Expanded portal tracts with fuzzy edges (UL 40X). IInterface hepatitis with plasma cells (UR 400X). Loose granuloma (LL 400X). Damaged bile duct (LR 400X).

Primary sclerosing cholangitis

• Abbreviated PSC.

Main article: Primary sclerosing cholangitis

Hereditary

Caroli disease

General

• Genetic disease.
  • Frequently associated with autosomal recessive polycystic kidney disease (ARPKD).
  • May be seen in isolation.

Clinical:

• Recurrent cholangitis.
• Recurrent cholelithiasis.
• Cholangiocarcinoma - seen in ~7% of cases.

Note:

• Caroli syndrome = Caroli disease + congenital hepatic fibrosis.

Gross

• Dilated bile ducts.

Microscopic

Features:

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

Image:

• Caroli disease (meddean.luc.edu).

Hereditary hemochromatosis

For secondary causes see secondary hemochromatosis.

Main article: Hereditary hemochromatosis

Wilson disease

Main article: Wilson's disease

Alpha-1 antitrypsin deficiency

• AKA alpha1-antiprotease inhibitor deficiency.

Main article: Alpha-1 antitrypsin deficiency

Other

Budd-Chiari syndrome

• AKA hepatic vein obstruction.

General

• Hepatic outflow obstruction.

Clinical triad:

• Ascites.
• Abdominal pain.
• Hepatomegaly.

Etiology:

• ~50% have a myeloproliferative disease.
• May be due to mass effect from a tumour.

Clinical DDx:

• Hepatic veno-occlusive disease.

Microscopic

Features:

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

DDx congestion:

• Congestive heart failure (congestive hepatopathy).
• Constrictive pericarditis.

Vanishing bile duct syndrome

• AKA bile duct loss, AKA ductopenia.

General

• Fatal.

DDx:

• Primary biliary cirrhosis.
• Primary sclerosing cholangitis.
• GVHD.
• Drugs.
• Chronic rejection.

Microscopic

Features:

• 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.

Extrahepatic biliary obstruction

Early extrahepatic biliary obstruction, demonstrated radiographically, transient, with rise in bilirubin, alkaline phosphatase, and transaminases. Pure canalicular cholestasis near terminal hepatic venules also seen in acute hepatitis, drug reactions, benign recurrent cholestasis, pregnancy, sepsis, & lymphomas. Sinusoidal dilatation, circular spaces of hepatocytes, small portal triads(UL 40X). Bile in hepatocytes about central vein & in plugs in canaliculi [yellow arrowhead] (UR 400X). Trichrome shows fibrosis about central vein (LL 400X). PAS with diastase shows portal triads with mild edema and chronic inflammation, without tortuous bile duct (LR 400X).

Changes of extrahepatic biliary obstruction, months duration. Expanded inflamed portal triads, swollen hepatocytes (UL 40X). Edematous stroma, proliferating ductules [yellow arrowheads], PAS-D macrophages [red arrowhead] (UR PAS with diastasse, 200X). Disordered, often swollen hepatocytes,some with feathery degeneration (net like spaces in cytoplasm) [blue arrowhead], rare Councilman body [green arrowhead] (LL 400X). Bile in hepatocytes [cyan arrrowhead] & in canaliculi [purple arrowheads]. Empty acinar spaces bounded by hepatocytes [orange arrowhead] (LR 400X).

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.

Gross

• "Nutmeg" liver - yellow spotted appearance.

Microscopic

Features:

• 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.

DDx:

• Hemangioma of the liver - should be focal lesion.

Images

• 

  Mild congestive hepatopathy. (WC)

Centrilobular necrosis (seen in circulatory failure and with toxins/drugs). PAS without diastase shows ovoids of necrosis {UL 40X). Necrosis with central vein [yellow arrowhead], inflammatory cells, residual Councilman body [green arrowhead], and hepatocyte with mitotic figure [red arrowhead] (UR 400X). Trichrome highlights fibrosis about central vein [yellow arrowhead] & shows beginning scar formation [green arrowheads]. Note residual atrophic hepatocytes [blue arrowheads] (LL 400X). Portal triads are largely unaffected (LR 400X)

Drug-induced liver disease

• AKA drug-induced liver toxicity.

Main article: Drug-induced liver disease

Focal nodular hyperplasia

• Abbreviated FNH.

Main article: Focal nodular hyperplasia

Nodular regenerative hyperplasia

General

• Associated with renal transplants, bone marrow transplants and vasculitides.
• Can lead to portal hypertension and many of the associated complications.

Etiology

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

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

Gross

• Diffuse nodularity - whole liver.

Microscopic

Features:

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

Sinuosoidal obstruction syndrome

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

General

• Term for obstruction due to toxicity from a chemotherapeutic agent.

Clinical DDx:

• Budd-Chiari syndrome.

Microscopic

Features:

• Subendothelial swelling in hepatic venules.

Negatives:

• No thrombosis.

Ascending Cholangitis

General

• Term for infection of bile ducts, usually due to obstruction

Clinical DDx:

Microscopic

Images

Ascending cholangitis case for Libre Pathology

Ascending cholangitis. Edematous triads, leukocyte speckled (UL), are expanded amid relatively undisturbed hepatocytes. Neutrophils lie within epithelium of proliferated bile ducts (UR). LL Acute inflammation spills out from some triads into the acini (LL). PAS with diastase stain (LR) better shows bile duct damage, with partial loss of the red line surrounding ducts & disorder of nuclei, as well as highlighting intra-epithelial neutrophils. Original oculars. UL 4X, UR 40X, LL 40X, LR 40X

Polycystic kidney disease and the liver

Main article: Cystic kidney disease

General

Complications of PKD in the liver:

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

Cysts:

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

Microscopic

Features:

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

Images:

• Von Meyenburg complex - bile duct hamartoma (WC).
• Bile duct hamartoma (WC).

Notes:

• Appearance on ultrasound and CT (hypodense) - similar to metastases.

Peliosis hepatis

General

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

Microscopic

Features:

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

Peliosis hepatis. Hemorrhage at left end, dilated sinusoids elsewhere (UL 20X). Ramifying dilated sinusoidal spaces (UR 100X). PAS with diastase shows flat lining (LL 400X). Necrotic hepatocytes in cords, presumably due to pressure (LR 400X).

Total parenteral nutrition

• Abbreviated TPN.

General

• Indication: short gut syndrome, others.

Microscopic

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

Features (classic):

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

Giant cell hepatitis

• AKA neonatal giant cell hepatitis.

See: Giant cell hepatitis.

Hepatic amyloidosis

Main article: Amyloidosis

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

General

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

Microscopic

Features:

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

DDx:

• Fibrolamellar hepatocellular carcinoma.

Images

• 

  Amyloidosis of the liver - low mag. (WC)

• 

  Amyloidosis of the liver - intermed. mag. (WC)

• 

  Amyloidosis of the liver - high mag. (WC)

• 

  Amyloidosis of the liver - very high mag. (WC)

Amyloidosis. Amorphous material replaces hepatic parenchyma [UL 4X]. Material barely stains blue on trichrome [UR 10X] Material stains red on unpolarized Congo Red [LL 40X] Material stains apple green on polarized Congo Red [LR 40X]

Stains

• Congo red +ve.

Fulminant hepatic necrosis

General

Etiology:

• Viral, i.e. Hepatitis A, Hepatitis B; Hepatitis C - extremely rare.
• Trauma.
• Shock.

Microscopic

Features:

• Hepatocyte necrosis.
• Bile duct proliferation.

DDx:

• Cholangiocarcinoma.
• Angiosarcoma.

Secondary hemochromatosis

For the hereditary one see hereditary hemochromatosis.

General

• Iron overload secondary to blood transfusions for hereditary or acquired anemia.
  • Primary hemochromatosis due to a defect in iron processing - called hereditary hemochromatosis.
• Imaging considered the best test, as iron deposition is patchy.

Selected hereditary causes:

• Thalassemia.
• Sickle cell anemia.
• Hereditary sideroblastic anemia.

Selected acquired causes:

• Myelodysplastic syndromes
• Myelofibrosis
• Aplastic anemia, intractable.

Microscopic

See hereditary hemochromatosis.

Hepatic sarcoidosis

Main article: Hepatic sarcoidosis

See also

• Pancreas.
• Gastrointestinal pathology.
• Liver neoplasms.
• Liver.