Hepatitis. Liver Toxic Damage. Liver Steatosis

Liver Steatosis (Fatty Liver disease):

Fatty liver is the accumulation of triglycerides and other fats in the liver cells. The amount of fatty acid in the liver depends on the balance between the processes of delivery and removal. In some patients, fatty liver may be accompanied by hepatic inflammation and liver cell death (steatohepatitis). Potential pathophysiologic mechanisms for fatty liver include the following:

• Decreased mitochondrial fatty acid beta-oxidation

• Increased endogenous fatty acid synthesis or enhanced delivery of fatty acids to the liver

• Deficient incorporation or export of triglycerides as very low-density lipoprotein (VLDL)

 

Pathologic changes observed in patients with alcoholic liver disease (ALD) can be divided into the following 3 groups:

• Alcoholic fatty liver (simple steatosis)

• Alcoholic hepatitis

• Alcohol-related cirrhosis

 

Alcoholic fatty liver is an early and reversible consequence of excessive alcohol consumption. Fatty liver develops in every individual who consumes more than 60 g of alcohol per day. Large amounts of alcohol enhance lipolysis through direct stimulation of the adrenal-pituitary axis. In addition, chronic ethanol ingestion inhibits oxidation of fatty acids in the liver and release of VLDL into the blood. All of these mechanisms favor steatosis.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Liver Toxic Damage: 

Drugs are an important cause of liver injury. More than 900 drugs, toxins, and herbs have been reported to cause liver injury, and drugs account for 20-40% of all instances of fulminant hepatic failure. Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death. Drug-induced hepatic injury is the most common reason cited for withdrawal of an approved drug. Physicians must be vigilant in identifying drug-related liver injury because early detection can decrease the severity of hepatotoxicity if the drug is discontinued. The manifestations of drug-induced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure.

Acute hepatocellular injury: Manifestations of acute liver injury may range from spotty necrosis to fulminant liver failure. Spotty necrosis resembles classic viral hepatitis and involves all acinar zones. Hepatocellular injury consists of ballooning degeneration or apoptosis with eosinophils, especially in cases of peripheral eosinophilia.

Chronic hepatocellular injury: Drug-induced chronic changes manifest many forms.

1. Pigment accumulation

2. Steatosis, steatohepatitis, and phospholipidosis

3. Hepatic fibrosis and cirrhosis

Acute cholestasis: Cholestasis is defined as a reduction in bile flow resulting from reduced secretion or obstruction of the biliary tree. If any evidence indicates hepatocellular injury, it is called cholestatic hepatitis.

Chronic cholestasis: Histology shows chronic portal inflammation and degeneration of the bile duct referred to as progressive ductopenia or vanishing bile duct syndrome. Most cases of drug-induced cholestasis are followed by rapid clinical and biochemical recovery upon withdrawal of the drug.

Granulomatous hepatitis: Most of these reactions consist of noncaseating epithelioid granulomas located in periportal or portal areas. This injury is usually transient and causes no sequelae.

Autoimmune hepatitis: Histology reveals active necroinflammatory lesions with prominent plasma cells. Females are affected more often than males. Autoimmune hepatitis manifests insidiously as fatigue, anorexia, weight loss, jaundice, ascites, portal hypertension, hepatomegaly, and splenomegaly.

Vascular lesions/venoocclusive disease: Drugs can injure any component of the liver, including the sinusoids, hepatic veins, and hepatic arteries. 

Neoplastic lesions: Focal nodular hyperplasia and hepatocellular adenomas have been well described since the advent of oral contraceptive steroids. 

 

Hepatitis:

Hepatitis, a general term referring to inflammation of the liver, may result from various causes, both infectious (ie, viral, bacterial, fungal, and parasitic organisms) and noninfectious (eg, alcohol, drugs, autoimmune diseases, and metabolic diseases). Viral hepatitis is most commonly caused by hepatitis A virus(HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). These 3 viruses can all result in acute disease with symptoms of nausea, abdominal pain, fatigue, malaise, and jaundice.[1] Additionally, HBV and HCV can lead to chronic infection. Patients who are chronically infected may go on to develop cirrhosis and hepatocellular carcinoma (HCC). Adults with acute hepatitis A or B are usually symptomatic. Persons with acute hepatitis C may be either symptomatic or asymptomatic.

Typical symptoms of acute hepatitis are fatigue, anorexia, nausea, and vomiting. Very high aminotransferase values (>1000 U/L) and hyperbilirubinemia are often observed. Severe cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic synthetic function.

Fulminant hepatic failure (FHF) is defined as acute liver failure that is complicated by hepatic encephalopathy. In contrast to the encephalopathy associated with cirrhosis, the encephalopathy of FHF is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation in the brain, which leads to brain-cell swelling. The resulting brain edema is a potentially fatal complication of fulminant hepatic failure.

Hepatitis A

The incubation period of HAV is 15-45 days (average, 4 weeks). The virus is excreted in stool during the first few weeks of infection, before the onset of symptoms. Typical cases of acute HAV infection are marked by several weeks of malaise, anorexia, nausea, vomiting, and elevated aminotransferase levels. Jaundice develops in more severe cases. Some patients experience a cholestatic hepatitis, marked by the development of an elevated alkaline phosphatase (ALP) level, in contrast to the classic picture of elevated aminotransferase levels. Other patients may experience several relapses during the course of a year. Less than 1% of cases result in FHF. HAV infection does not persist and does not lead to chronic hepatitis.

Hepatitis B

HBV may be directly cytopathic to hepatocytes. However, immune system–mediated cytotoxicity plays a predominant role in causing liver damage. The immune assault is driven by human leukocyte antigen (HLA) class I–restricted CD8 cytotoxic T lymphocytes that recognize hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg) on the cell membranes of infected hepatocytes.

Hepatitis C

HCV has a viral incubation period of approximately 8 weeks. Most cases of acute HCV infection are asymptomatic. Even when it is symptomatic, acute HCV infection tends to follow a mild course, with aminotransferase levels rarely higher than 1000 U/L. Whether acute HCV infection is a cause of FHF remains controversial.

Approximately 15-30% of patients acutely infected with HCV lose virologic markers for HCV. In chronic hepatitis, patients may or may not be symptomatic, with fatigue being the predominant reported symptom. Aminotransferase levels may range from reference values (< 40 U/L) to values as high as 300 U/L. 

Patients with HCV-induced cirrhosis are also at increased risk for the development of HCC, especially in the setting of HBV coinfection.