Liver Diseases (Etiologies)

Liver diseases can be acute or chronic; chronic is defined as inflammation and/or fibrosis for at least 6 months. Recall that chronic liver disease is especially problematic when it leads to cirrhosis and portal hypertension. We can categorize liver diseases by the type of injury they cause:

• Hepatocellular injury, in which inflammation and necrosis affects the hepatocytes
• Obstructive (aka, cholestatic) injury, in which bile flow is inhibited
• Mixed injury

We can also categorize liver diseases by the types of morphological damage that occurs:

• Toxic/necrosis
• Fatty
• Inflammatory (hepatitis)
• Vascular injury
• Cholestasis
• Granuloma formation

Signs and symptoms of liver disease vary by stage: Early in their course, most patients are asymptomatic. As damage accumulates, they may experience right upper abdominal pain (aka, liver pain), poor appetite/nausea (which can lead to malnutrition), and hyperbilirubinemia (particularly jaundice) In end-stage liver disease, clinical manifestations of cirrhosis and portal hypertension, such as varices and ascites, may appear. Diagnosis of liver disease is complex; we use a battery of blood tests to evaluate ALT (alanine aminotransferase), AST (aspartate transaminase), AlkP (ALP, alkaline phosphatase), bilirubin, albumin, and prothrombin time. Learn more about Liver pathology serum markers. Liver biopsy is the "gold standard" of liver disease evaluation, as the type and degree of damage is used to assess the stage and grade of disease. "Grading" assesses liver disease the severity and prognosis for survival. Examples include the Model for End-Stage Liver Disease (MELD) and the Child-Pugh score. The Model for End-Stage Liver Disease (MELD), which is based on laboratory values, is used to evaluate patients in end-stage liver disease for organ transplant. The Child-Pugh score is based on laboratory values and the presence/absence of signs of cirrhosis, including encephalopathy and ascites, to determine the severity of liver disease. Chronic liver disease "staging" tells us how far along the disease has progressed (from inflammation, to fibrosis, to scarring & impaired function, to failure). Acute or chronic liver injury in response to drugs, supplements, or medicinal herbs. Damage can be direct or idiosyncratic; direct is dose-dependent and predictable, whereas idiosyncratic varies by individual, is not-dose dependent, and is not predictable. (be aware that some authors discuss direct, indirect, and idiosyncratic, others use "intrinsic" vs idiosyncratic). Injury can lead to hepatitis or cholestatic injury, with various morphologies depending on the offending agent. Acetaminophen is the most common cause of direct damage; when taken in large doses, acetaminophen metabolism releases reactive metabolites that accumulate and lead to hepatic apoptosis and necrosis. Other common classes of drugs that cause hepatic injury include antibiotics (amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, etc.); cardiovascular drugs (statins and amiodarone), and anti-seizure drugs (valproate, phenytoin). Fatty liver is a top cause of liver disease world-wide; it includes alcoholic and non-alcoholic etiologies. Generalized progression: First, fat accumulates in hepatocytes, which bloats the cells and displaces their nuclei. Then, lipotoxicity from the accumulated fat causes inflammation and necrosis, which triggers repair processes; we may see Mallory-Denk bodies, which are cytoplasmic hyaline inclusions found in many chronic liver diseases. Cycles of damage and repair lead to fibrosis, which, over time, can create scarring and impair liver functioning – this is cirrhosis, stage 3 liver disease. Be aware that this progression does not occur in all individuals; the reasons for this are under investigation. Alcoholic liver disease occurs in patients with chronic or binge drinking habits. Lab results will show elevated AST to ALT ratios. Alcoholic liver disease exists on a spectrum of mild to severe: 1. Alcoholic fatty liver refers to the accumulation of fat in the hepatocytes; it is often asymptomatic. 2. Alcoholic steatohepatitis refers to fatty liver with inflammation and fibrosis. 3. Alcoholic hepatitis is the most severe form; patients may start to experience signs and symptoms of cirrhosis and portal hypertension, with possible fever. Chronic Hepatitis C infection is an important co-morbidity. Alcohol cessation is always recommended. In the early stages, alcohol cessation can allow the liver to heal itself. Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder associated with insulin resistance. Patients should be checked for other metabolic disorders, and alcohol use should be ruled out. Non-alcoholic fatty liver disease has essentially two pathways: 1. Triglycerides accumulate in the hepatocytes and cause bloating and cell distortion (similar to the first image in our illustration). 2. In some individuals, NAFLD progresses to non-alcoholic steatohepatitis (NASH), in which fat accumulation leads to lipotoxicity with eventual fibrosis and possibly cirrhosis (similar to the transition from alcoholic steatohepatitis to hepatitis). Unfortunately, there are no broadly applicable treatments available for non-alcoholic fatty liver disease; weight loss is thought to reduce hepatic fat deposits and inflammation, and some pharmaceutical options are available for select patients (anti-diabetic drugs and vitamin supplements, which are not appropriate for everyone). Causes hepatocellular necrosis and can be acute or chronic, depending on the viral agent: Hepatitis A and Hepatitis E are typically acute infections, whereas Hepatitis B, Hepatitis C, and Hepatitis B + D are chronic infections. Look for elevated aminotransferases and specific antibodies in the blood, and note that viral hepatitis can cause fever as well as other symptoms. For more on viral hepatitis, click here: Viral hepatitis Autoimmune disorders that result in bile accumulation, which damages hepatocytes. Patients present with fatigue, itching, jaundice, and other manifestations of hyperbilirubinemia. Primary biliary cholangitis (PBC) destroys the bile ducts. We look for anti-mitochondrial antibodies in laboratory results; other unique signs include hypercholesterolemia and xanthomas. PBC is most commonly diagnosed in women in their 40s-60s. Primary sclerosing cholangitis is characterized by inflammation with scarring and narrowing (sclerosing) of the bile ducts, and is associated with irritable bowel disease. The presence of p-ANCA supports the diagnosis. This is a poorly understood condition characterized by necrosis and inflammation. We can look for antinuclear antibodies (ANA) and antibodies against smooth muscle tissue (ASMA). Because it is an autoimmune disorder, we treat it with immune suppressants. This is an inherited disorder of excess iron absorption from the small intestine. We diagnose with blood iron and genetic tests. Iron overload affects a variety of organ systems, and can cause hypogonadism (with sexual dysfunction), skin "bronzing," arthropathies, fatigue, diabetes mellitus, liver damage, and cardiomyopathy. An inherited disorder of copper storage. Excess copper particularly affects the liver, brain, and eyes, leading to abdominal pain, jaundice, weakness, movement and psychiatric disorders, and seizures. Look for Kayser-Fleisher ring around the iris; these brownish-golden rings are created by copper deposition in the cornea, and typically begin their formation superiorly, under the eyelid. For more on the genetic defects, mechanisms, and clinical outcomes of Wilson's disease, click here: Wilson's Disease The most common primary liver cancer, and is typically preceded by one of the chronic liver diseases we've discussed in this tutorial, especially when cirrhosis is present. Thus, we need to regularly screen patients with chronic liver disease for cancer development. For full references, please see the tutorial on Liver Diseases.