What is the relationship between liver disease and alcohol use?

The Liver

The liver is the largest organ in the body and the only organ able to regenerate itself. Performing more than five hundred vital functions, it is the conduit where blood from the stomach and intestines passes and where toxic substances and waste products are removed from the blood. The liver is responsible for protein, carbohydrate, and lipid metabolism and for detoxification and metabolism of ethanol and its toxic by-products.

The liver consists of two main lobes containing small units called lobules. These hexagonal plate-like structures are made up of hepatocytes (liver cells) and are attached to interconnecting ducts that end in the hepatic duct. Hepatocytes constitute the functional component of the liver, making up 70 to 80 percent of its cytoplasmic mass, and the cells are damaged by prolonged alcohol ingestion. A connective tissue capsule covering the liver acts as scaffolding; its branching extends throughout the liver as septae, enabling vessels and bile ducts to traverse the liver.

Disease Manifestation

ALD is a spectrum of evolving liver injuries, progressing from mild steatosis and fatty infiltration to hepatitis and fibrosis, and finally to cirrhosis, which evolves to complications of portal hypertension, hepatic encephalopathy, or hepatocellular carcinoma. Although ALD is often devoid of clinical symptoms and best observed histopathologically, the course of the disease can be insidious.

Steatosis, the abnormal retention of lipid (fat) within a cell, is the earliest manifestation of ALD and is seen in 90 percent of heavy drinkers. The lipid droplets are mostly triglycerides, and as they accumulate in hepatocytes, the liver becomes infiltrated with fatty deposits—hence, the term fatty liver
. Injury is most evident in the perivenular area (zone three), a diamond-shaped area of the hepatic lobule located around central veins. Fatty liver is a relatively benign condition that reverses itself quickly with abstinence.

Continued drinking causes necroinflammation and the onset of alcoholic hepatitis (AH), an acute form of alcohol-induced liver injury, marked by intralobular inflammation and necrosis. AH is characterized by a group of morphological changes in cell integrity, ranging in severity from detection of distinct necroinflammatory components (steatohepatitis) to evidence of biochemical damage and lesions to fulminant liver failure, triggering sudden and rapid deterioration of liver function.

The pattern of fatty liver development is macrovesicular, such that swelling of the cytoplasm occurs; this process is called ballooning degeneration and it reflects widespread disturbances in lipoprotein transport in and out of hepatocytes. With ballooning, fat accumulation inside hepatocytes is so large it distorts the cell’s nucleus and displaces the cytoplasm. In staining it appears as single-shaped white spaces or vacuoles. Ballooning leads to lytic necrosis, causing cell contents to decompose, with subsequent condensation of reticulin fibers (fibrosis). Common lesions in AH are neutrophilic infiltrates, Mallory hyaline inclusions or bodies, megamitochondria, and lipogranulomas that form from ruptured hepatocellular fat.

Clinical diagnosis of AH remains rather nebulous, as there are no positive markers or reliable tests that differentiate simple fatty liver from steatohepatitis or more advanced stages of ALD. The short-term mortality rate for patients with severe AH is high, and the disease is a precursor to cirrhosis, with an associated long-term risk nine times higher in AH than in fatty liver alone.

Fibrosis

Fibrosis is an exaggerated response to the wound-healing process elicited by liver damage involving the production of excessive type 1 collagen and other extracellular matrix (ECM) proteins and their deposition as scar tissue. Collagen deposition occurs primarily in an area of the liver known as the space of Disse. The fibrosis common to ALD is called sclerosing hyalin necrosis and involves wide pericentral areas of fibrosis extending to portal fields.

With overspreading necrosis, the ECM becomes overwhelmed and loses its ability to express enzymes that degrade lesions. This results in unbalanced synthesis and decomposition of collagen, causing proliferation of connective tissue and, over time, increases to wider bands of collagen that form bridging fibrosis. Lesions then span between septae and cause disturbances in lobular structure, loss of hepatocytes, and deterioration in liver function.

Hepatic stellate cells (HSCs) are known to generate fibrosis. Normally dormant, HSCs become activated in response to liver injury. Activated HSCs are differentiated myofibroblast-like cells with a changed phenotype, characterized by proliferative, fibrogenic, and contractile properties. The process affects a cascade of histologic events in which HSCs elicit inflammatory signaling, cytokine release, and matrix metalloproteinase dysregulation, resulting in increased accumulation of ECM and further fibrosis.

Liver fibrosis is reversible and liver transplantation improves survival. However, most transplant centers do not recommend transplants unless a patient demonstrates a minimum of six months of abstinence from alcohol.

Cirrhosis

Cirrhosis is a diffuse pathologic process of architectural disorganization involving the entire liver, whereby normal liver architecture is replaced by abnormal structures called regenerative nodules. These nodules are completely surrounded by fibrous-band bridging between portal tracts. Cirrhosis usually develops over many years and produces a nodular, firm liver. In ALD, cirrhosis is usually micronodular and most prominent in the central vein area. Often called Laennec’s cirrhosis, it is characterized by a fine mesh-like pattern of small uniform yellow nodules and narrow, regular fibrous septa.

Decompensated cirrhosis occurs when liver function is overridden by architectural remodeling and is accompanied by complications of portal hypertension or hepatic encephalopathy. Portal hypertension causes phlebosclerosis (hardening of venous walls), resulting from abnormal blood flow patterns of cirrhotic liver, and its effects extend to other organs. Encephalopathy is a clinical state of disordered cerebral function caused by impaired hepatic metabolic function. Decompensated cirrhosis is often further complicated by hepatocellular carcinoma, is irreversible, and has high mortality.

By eliminating alcohol before cirrhosis develops, it is possible for the liver to heal—a sobering fact, considering ALD claimed 18,146 lives in the United States in 2013, according to mortality data from the US Centers for Disease Control and Prevention.

Bibliography

“Alcoholic Liver Disease.” Cleveland Clinic: Current Clinical Medicine. Ed. William Carey. 2nd ed. Philadelphia: Saunders, 2010. Print.

"Cirrhosis." National Institute of Diabetes and Digestive and Kidney Diseases. Natl. Inst. of Diabetes and Digestive and Kidney Diseases, 23 Apr. 2014. Web. 27 Oct. 2015.

"FastStats: Alcohol Use." Centers for Disease Control and Prevention. CDC, 20 July 2015. Web. 27 Oct. 2015.

Feldman, Mark, Lawrence Friedman, and Lawrence Brandt. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th ed. Philadelphia: Saunders, 2010. Print.

Schiff, Eugene, Michael Sorrell, and Willis Maddrey, eds. Schiff’s Diseases of the Liver. 10th ed. Philadelphia: Lippincott, 2006. Print.