Serdar Balcı

Inflammatory, Toxic, Alcoholic and Metabolic Diseases of Liver

Serdar BALCI, MD


Drug- or Toxin-Induced Liver Disease

Drug-induced liver disease

Robbins Basic Pathology

Drug reactions

Many drugs cause hepatic injury

**For updated information **



Depending on the toxic material different zones may be affected

If the toxin is a metabolite of a drug then it may accumulate in zone 3 and most severe effect is seen in zone 3

Robbins Basic Pathology

Robbins Basic Pathology

**Acetaminophen overdose. Confluent necrosis is seen in the perivenular region (zone 3) **

Robbins Basic Pathology


Fatty Liver Disease

Hepatocellular Steatosis

Fatty liver disease. Macrovesicular steatosis is most prominent around the central vein and extends outward to the portal tracts with increasing severity. The intracytoplasmic fat is seen as clear vacuoles. Some fibrosis (stained blue) is present in a characteristic perisinusoidal “chicken wire fence” pattern.

Robbins Basic Pathology


More with alcohol use than in NAFLD

Hepatocyte ballooning

Mallory-Denk bodies

Neutrophilic reaction

clustered inflammatory cells

necrotic hepatocyte

**Mallory-Denk body **

Robbins Basic Pathology

**keratins 8 and 18 **

**ballooned hepatocytes **

Robbins Basic Pathology

Neutrophil infiltration

Predominantly neutrophilic infiltration may permeate the lobule

Accumulate around degenerating hepatocytes, particularly those containing Mallory-Denk bodies

Lymphocytes and macrophages also may be seen in portal tracts or parenchyma

Steatohepatitis with fibrosis

First in the centrilobular region, central vein sclerosis

Perisinusoidal scar appears in the space of Disse of the centrilobular region

Spreads outward, encircling individual or small clusters of hepatocytes in a chicken wire fence pattern

Link to portal tracts

Condense to create central-portal fibrous septa

Liver takes on a nodular, cirrhotic appearance

Classic micronodular or Laennec cirrhosis

Course of Fatty Liver Disease

Steatosis or fatty change imparts a yellow to orange cast to the liver parenchyma

Autopsy Pathology: A Manual and Atlas

Alcoholic cirrhosis

Diffuse nodularity. Average nodule size is 3 mm. Greenish because of bile stasis

Robbins Basic Pathology

Steatohepatitis leading to cirrhosis. Small nodules are entrapped in blue-staining fibrous tissue; fatty accumulation is no longer seen in this “burned-out” stage

Robbins Basic Pathology

Alcoholic liver disease

Steatosis, alcoholic hepatitis, and fibrosis may develop independently

Not necessarily represent a continuum of changes

Hepatocellular carcinoma arises in 10-20% of patients with alcoholic cirrhosis

Alcoholic liver disease

Robbins Basic Pathology

Causes of hepatocellular steatosis

Causes of alcoholic hepatitis

Nonalcoholic Fatty Liver Disease (NAFLD)

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Drug/Toxin-Mediated Injury with Steatosis



Hereditary Hemochromatosis

HFE gene

Located on the short arm of chromosome 6

Encodes a protein that is similar in structure to MHC class I proteins

Expression of the mutated HFE protein on small intestinal enterocytes leads to inappropriately upregulated absorption of iron and its binding to transferrin

HFE and the other genes involved in less common forms of hereditary hemochromatosis all regulate the levels of hepcidin, the iron hormone produced by the liver

Hepcidin normally down-regulates the efflux of iron from the intestines and macrophages into the plasma and inhibits iron absorption

When hepcidin levels are reduced there is increased iron absorption

Excessive iron directly toxic to tissues

Lipid peroxidation by iron-catalyzed free radical reactions

Stimulation of collagen formation

Direct interactions of iron with DNA


**Accumulation of iron results in a rusty brown liver **

Autopsy Pathology: A Manual and Atlas

Robbins Basic Pathology

Iron is a direct hepatotoxin, and inflammation is characteristically absent

Liver typically is slightly larger than normal, dense, and chocolate brown

Fibrous septa develop slowly

Cirrhosis in an intensely pigmented (very dark brown to black) liver

Dry weight:

Normal iron content of unfixed liver tissue <1000 µg/g dry weight

Clinically evident iron overload of hereditary hemochromatosis exhibit >10,000 µg/g dry weight of iron

>22,000 µg/g dry weight are associated with the development of fibrosis and cirrhosis

Wilson Disease

Autosomal recessive

Accumulation of toxic levels of copper

Liver, brain, and eye

Loss-of-function mutations in the ATP7B gene

Chromosome 13, encodes an ATPase metal ion transporter that localizes to the Golgi region of hepatocytes

Normal copper physiology

Absorption of ingested copper (2 to 5 mg/day)

Plasma transport in complex with albumin

Hepatocellular uptake, followed by binding to an α2 -globulin (apoceruloplasmin) to form ceruloplasmin

Secretion of ceruloplasmin-bound copper into plasma, where it accounts for 90% to 95% of plasma copper

Hepatic uptake of desialylated, senescent ceruloplasmin from the plasma, followed by lysosomal degradation and secretion of free copper into bile

α1-Antitrypsin Deficiency

Autosomal recessive disorder

Abnormally low serum levels

The major function of AAT is the inhibition of proteases

Pulmonary emphysema

Hepatic disease results from retention of mutant AAT in the liver

AAT synthesized predominantly by hepatocytes

Most allelic variants produce normal or mildly reduced levels of serum AAT

Homozygotes for the Z allele ( PiZZ genotype) have circulating AAT levels that are only 10% of normal levels

PiMZ heterozygotes have intermediate plasma levels of AAT

The PiZ polypeptide contains a single amino acid substitution that results in misfolding of the nascent polypeptide in the hepatocyte endoplasmic reticulum

Mutant protein cannot be secreted by the hepatocyte, it accumulates in the endoplasmic reticulum and triggers unfolded protein response, lead to induction of apoptosis

Marked cholestasis with hepatocyte necrosis in newborns

Childhood cirrhosis

Chronic hepatitis or cirrhosis that becomes apparent only late in life

Hepatocellular carcinoma develops in 2% to 3% of adults with PiZZ genotype, usually but not always in the setting of cirrhosis

The treatment and cure for the severe hepatic disease are orthotopic liver transplantation

α1-Antitrypsin deficiency

Round to oval cytoplasmic globules composed of retained AAT

Glycoprotein stains with PAS

Robbins Basic Pathology