11. Hepatic lesions caused by circulatory disorders. Nonviral inflammatory diseases of the liver. Drug hepatopathies

Written by ms. worldwide, edited by Nikolas.

The liver is the largest parenchymal organ, with a weight between 1000-1300 g. The most important jobs of the liver are synthesis, detoxication and excretion.

Impaired bloow flow to the liver

Hepatic artery infarct

Infarcts in the liver are rare, due to the double blood supply of to the liver. Therefore, an interruption of the main hepatic artery does not always cause ischemic necrosis because the retrograde arterial flow through the accessory vessels and portal venous supply may sustain liver parenchyma. However, this doesn’t apply for a transplanted liver where a complication can be hepatic artery thrombosis. The transplanted liver parenchyma will die.

Thrombosis or compression of intrahepatic branches of the hepatic artery may also result in localized parenchymal infarct.

Portal vein obstruction and thrombosis

Extrahepatic portal vein obstruction can arise from the following scenarios:

• Pancreatitis which causes a thrombosis in the splenic vein that moves into the portal vein.
• Thrombogenic diseases
• Postsurgical thromboses
• Cirrhosis – does not obstruct directly but slows down the blood flow which increases the risk for thrombus formation.

Occlusion of the portal vein or its branches give symptoms like abdominal pain,  other manifistations of portal hypertension like esophageal varices. Ascites is rare because the block is presinusoidal, but when present are often massive and intractable.

Intrahepatic portal vein occlusions do not cause an ischemic infarction when acute but result in a sharply demarcated area of red-blue discoloration, called infarct of Zahn. There is no necrosis but congestion of sinusoids and atrophy of hepatocytes.

Impaired blood flow through the liver - passive congestion and centrilobular necrosis

The most common cause of impaired blow flow through the liver is by far cirrhosis. Physical occlusion of sinusoids (Sickle cell) or DIC can also occur.

Passive congestion of the liver (nutmeg liver) and central haemorrhagic necrosis are hepatic manifestations of systemic circulatory disorders. Right-sided cardiac failure, like in cor pulmonale, leads to congestion of the liver. Chronic congestion of the liver causes the morphology nutmeg liver, or hepar moschatum. If a patient with nutmeg liver also develops acute left ventricular failure there will be central haemorrhagic necrosis as well. You can study more about these conditions in the pathology 1 section.

Nutmeg liver doesn’t cause jaundice or liver disfunction but can be detected by a small elevation in serum aminotransferase levels.

Manifestations of impaired blodflow through the liver can be ascites (cirrhosis), esophageal varices (cirrhosis), hepatomegaly and as previously mentioned elevated levels of serum transaminases.

Hepatic vein outflow obstruction

Hepatic vein thrombosis – Budd-Chiari syndrome

The Budd-Chiari syndrome is a very rare condition (1 in one million) that results from occlusion of two or more major hepatic veins.  Occlusion causes the congestion of the liver, causing hepatomehaly, ascites and portal hypertension.

The risk factors for thrombosis here are usual risk factors for thrombus formation or mechanical obstruction:

• Hypercoagulable state
  • Polycythaemia vera (50% of cases)
  • Pregnancy
  • Oral contraceptives
  • Hypercoagulability due to cancer
• Invasion of cancers like renal cell carcinoma into the hepatic vein

The liver will swell and the capsule around it will become tense. The liver itself will look red-purplish. Histologically, we can see centrilobular congestion (nutmeg liver appearance) with centrilobular necrosis. The mortality is high.

Clinical findings in patients with these are hepatomegaly, ascites, and abdominal pain.

Sinusoidal obstruction syndrome

Sinusoidal obstruction syndrome, also called hepatic venooclusive disease is caused by damage to the sinusoidal epithelium, most commonly due to chemotherapy or radiation. Nowadays it’s often seen in people who undergo chemotherapy before a bone marrow transplant (as this chemotherapy is very intensive).

The damaged endothelium cells will slough and form thrombi, which block the sinusoidal flow. RBCs also spill into the space of Disse as there is no endothelium holding them back, while the damaged endothelium also cause proliferation of stellate cells and fibrosis of terminal branches of the hepatic vein.

The clinical presentation is similar to that of Budd-Chiari syndrome, involving hepatomegaly, ascites and portal hypertension.

Neonatal hepatitis

The neonatal hepatitis is a group of disorders in neonates which are characterized by:

• Hepatocellular dysfunction
• Cholestasis
• Conjugated hyperbilirubinemia

They all have very similar morphology as well:

• Balloonisation or focal necrosis of hepatocytes
• Multinucleated hepatocytes
• Lymphocytic infiltration in the portal area
• Proliferation of bile ducts

The neonatal hepatitis can be caused by several disease, like e.g. TORCH or metabolic causes. Let’s take a look at them.

• TORCH infections
• Metabolic causes
  • Alfa1-antitrypsin deficiency
  • Wilson disease – where excess copper is stored various tissues of the body, like the liver.
  • Galactosemia
  • Fructosaemia
  • Tyrosinemia
• Bile duct anomalies
  • Atresia of intra- or extrahepatic bile duct.
  • Alagille syndrome – autosomal dominant syndrome where there are too few bile ducts.
• Progressive familiar intrahepatic cholestasis (PFIC), which causes cholestasis due to defects in the biliary epithelial transporters.

Cholangitis

Cholangitis is an acute infection of the biliary tree, almost always caused by bacterial infection. It is usually caused by anything that can obstruct the bile flow, but most commonly choledocholithiasis, gall stones in the common bile duct. Other reasons for this can be surgery of the biliary tree, tumors and acute pancreatitis. The bacteria usually enter the biliary tract via the Sphincter of Oddi rather than through blood, and results in an ascending cholangitis, where the bacteria “climb upwards” in the biliary tree until the intrahepatic biliary ducts. The usual pathogens are:

• E. coli
• Klebsiella

The symptoms of cholangitis include fever, chills, abdominal pain and jaundice. If the cholangitis is severe enough, it develops into suppurative cholangitis where the purulent bile expands the bile ducts and gives a high risk of liver abscess formation and sepsis. Treatment is needed and includes antibiotics and drainage of the bile ducts.

Drug hepatopathies

Drugs are an important cause of liver injury, and many accepted drugs have been withdrawn from the market because they caused severe hepatopathies. Some drugs are hepatotoxic only in big doses and must be monitored closely by the doctor. We distinguish between direct and indirect hepatotoxic substances.

Direct hepatotoxic substances are called that because their metabolites directly cause damage to the liver. However, we can predict the damage, and know the dose that can be given without causing damage – their toxicity is dose dependent. Also, some persons are more exposed to develop diseases and injuries from these drugs than others. The onset of symptoms of injury is also short.

Some examples:

• Anabolic steroids
• Amantin
• Contraceptives
• Tetracyclines
• Methotrexate
• Paracetamol (Acetaminophen)
• Alfa-methyl-DOPA

Indirect hepatotoxic substances can cause damage because their substances can serve as haptens, initiating an immune reaction. They can also cause damage by altering the metabolism of the liver. This toxicity is not dose-depended so it’s hard to predict the dose and how an individual will react to the drug. There is also 1-2 weeks latency before the symptoms shows, and other allergic symptoms can appear as well.

Some examples:

• Contraceptives
• Anabolic steroids
• Antibiotics
• Halothane
• Chlorpromazine