Hepatocellular Necrosis
Elevation of ALT and AST indicates hepatocellular necrosis. The interpretation of these increases should consider the rate of rise, the severity (peak level), the AST/ALT ratio, and coexisting abnormalities in other LFTs and other investigations. ALT and AST are enzymes that catalyze the transfer of amino groups from alanine or aspartic acid to ketoglutaric acid to form pyruvic acid and oxaloacetic acid, respectively, during gluconeogenesis. ALT is localized primarily in the liver and confined to the cytoplasm, while AST can be released by the liver, myocardium, skeletal muscle, kidney, pancreas, and blood cells, and can be found in the cytoplasm and mitochondria. During hepatocellular injury they are released into the bloodstream. However, their increase is not always pathologic: they can be raised by vigorous physical activity, and rarely an isolated AST can be the result of the binding of the enzyme with an immunoglobulin forming a macro‐enzyme (macro‐AST) complex. The diagnostic specificity of mild‐to‐moderate increases in aminotransferases is poor, with many differential diagnoses being possible, whereas the spectrum of liver conditions indicated by markedly elevated aminotransferase levels (>2000 IU/l) narrows to viral (mostly hepatitis A and hepatitis B virus), ischemic (shock liver), and drugs. Autoimmune hepatitis can sometimes have an acute outset with striking elevation of aminotransferases. Rarely, bile duct stones can manifest as marked rise in aminotransferase, although this is followed by a rapid fall within 48 hours.
The AST/ALT ratio can often provide a clue to the diagnosis. In the majority of cases of hepatitis, the AST/ALT ratio is less or equal to 1. The AST/ALT ratio is typically greater than 2 during alcoholic hepatitis. This occurs because damage is primarily mitochondrial (thus more AST is released systemically) and ALT synthesis is more sensitive than AST to pyridoxal 5‐phosphate deficiency, a common finding in alcoholics, leading to lower serum ALT levels. Supplementation with pyridoxine in patients with alcoholic hepatitis results in a rise in the level of ALT. An AST/ALT ratio greater than 1 in patients without a history of alcoholism is suggestive of advanced fibrosis or cirrhosis. An AST/ALT ratio greater than 4 is observed in patients with fulminant Wilson disease.
Cholestasis
Cholestasis is an overarching term applied to conditions in which there is impairment of bile formation and/or bile flow. It occurs where there is a failure at any point along the biliary tree, between the basolateral (sinusoidal) membrane of the hepatocyte and the ampulla of Vater, as a result of congenital or acquired injuries, that leads to impaired secretion of bile such that biliary constituents spill into blood. It may result from (i) hepatocellular and/or cholangiocellular secretory defects or (ii) obstruction of bile ducts by bile duct lesions, stones or tumors, but may also be related to mixed mechanisms in conditions such as PBC or PSC.
ALP and GGT are markers of cholestasis. ALP is a ubiquitous membrane‐bound glycoprotein that catalyzes the hydrolysis of phosphate monoesters at basic pH values. Liver and bone are the major source of serum ALP. The liver isoenzyme is located on the canalicular side of the hepatocyte plasma membrane and the luminal surface of bile duct epithelium. Serum ALP elevation more than three times normal strongly suggests cholestasis if bone disease is absent and GGT is elevated. In patients with cholestasis, the ALP elevation is triggered by increased synthesis and release of the enzyme into serum rather than impaired biliary secretion. BAs build up in hepatocytes and solubilize the plasma membrane, thereby resulting in release of ALP. The half‐life of serum ALP is 5–7 days, and therefore serum ALP remains elevated for several days after resolution of the biliary obstruction. ALP is not used as a marker of cholestasis in adolescent and pregnant women since ALP in these conditions can be raised as a consequence of rapid bone growth and placental growth. Chronic renal failure can result in elevation of the intestinal ALP isoenzyme. In patients with raised ALP, hyperthyroidism should be ruled out. Rarely, ALP can be identified in patients with underlying malignancy not involving either liver or bones. This is the Regan isoenzyme, biochemically different from the liver isoenzyme, that has been described in lung cancer, Hodgkin disease, and renal cell carcinoma. Finally, ALP should be tested after fasting since its level can rise after a fatty meal.
GGT is an enzyme that can be induced by several stimuli such as drugs and alcohol. It is mainly localized in hepatocytes and biliary epithelia, and is also present in extrahepatic tissues such as kidney, spleen, pancreas, heart, lung, and brain, but not bone. The lack of GGT in bone can be used to distinguish a liver source from a bone source of a raised ALP. GGT is more liver specific than ALP, although during cholestasis is less specific since it can be influenced by other factors such as alcohol, fat, and drugs. A GGT/ALP ratio over 2.5 may point to alcohol abuse, although up to one‐third of those who abuse alcohol (>80 g/day) have a normal GGT. A normal GGT in patients with elevated liver ALP isoenzyme should raise the suspicion of benign recurrent intrahepatic cholestasis.
References
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2 Concepts of Autoimmunity Relevant to Autoimmune Liver Diseases
Isaiah G. Roepe1 and John M. Vierling2
1 Baylor College of Medicine, Houston, TX, USA
2 Departments of Medicine and Surgery, Section of Gastroenterology and Hepatology, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
Abstract
Knowledge of the concepts of autoimmunity can aid gastroenterologists and hepatologists in management and counseling of patients with autoimmune liver diseases and in understanding the rationales and sites of action of therapies. This chapter addresses major themes: innate and adaptive immunity in the context of the liver as an immune organ; generation and maintenance of tolerance to autoantigens; and risk factors for autoimmunity. The themes discussed also include: loss of immune tolerance to autoantigens and perpetuation of autoimmune diseases; and
