Diagnosis of Hepatitis
Hepatitis is diagnosed by assessing an individual's symptoms, physical exam, and medical history, in conjunction with blood tests, liver biopsy, and imaging. Blood testing includes blood chemistry, liver enzymes, serology and nucleic acid testing. Abnormalities in blood chemistry and enzyme results may be indicative of certain causes or stages of hepatitis. Imaging can identify steatosis of the liver but liver biopsy is required to demonstrate fibrosis and cirrhosis. (Newer technology, the Fibroscan, can non-invasively measure fibrosis and cirrhosis.) A biopsy is unnecessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications caused by liver biopsy.
|Liver chemistry test||Clinical implication of abnormality|
|Alanine transaminase (ALT)||Hepatocellular damage|
|Aspartate transaminase (AST)||Hepatocellular damage|
|Prothrombin time||Impaired synthetic function|
|Albumin (ALB)||Impaired synthetic function|
|Gamma-glutamyl transpeptidase (GGT)||Cholestasis|
|Lactate dehydrogenase (LDH)||Hepatocellular damage|
Diagnosis of viral hepatitis
Viral hepatitis is mostly diagnosed through clinical laboratory testing, (antibody and PCR testing). Some of these tests react with the virus or parts of the virus, such as the Hepatitis B surface antigen test or nucleic acid tests. Many of the tests are serological tests that react to the antibodies formed by the immune system. For some major causes of viral hepatitis, such as Hepatitis B, there are multiple serological tests used that provide additional information for diagnosis.
Several diseases can present with signs, symptoms, and/or liver function test abnormalities similar to hepatitis. In severe cases of alpha 1-antitrypsin deficiency (A1AD), excess protein in liver cells causes inflammation and cirrhosis. Some metabolic disorders cause damage to the liver through a variety of mechanisms. In hemochromatosis and Wilson's disease toxic accumulation of dietary minerals results in inflammation and cirrhosis.
Normal Hepatic Histology (Tissue structure and function)
A hepatic lobule is a small division of the liver defined at the histological scale. It should not be confused with the anatomic lobes of the liver (caudate lobe, quadrate lobe, left lobe, and right lobe), or any of the functional lobe classification systems.
The two-dimensional microarchitecture of the liver can be viewed from multiple different perspectives:
|classical lobule||hexagonal; divided into concentric centrilobular, midzonal, periportal parts||anatomical|
|portal lobule||triangular; centered on a portal triad||bile secretion|
|acinus||elliptical or diamond-shaped; divided into zone I (periportal), zone II (transition zone), and zone III (pericentral)||blood flow and metabolic|
The term "hepatic lobule", without qualification, typically refers to the classical lobule.
Oxygenation zones are inside the diamond-shaped acinus
From a metabolic perspective, the functional unit is the hepatic acinus (terminal acinus), each of which is centered on the line connecting two portal triads and extends outwards to the two adjacent central veins. The periportal zone I is nearest to the entering vascular supply and receives the most oxygenated blood, making it least sensitive to ischemic injury while making it very susceptible to viral hepatitis. Conversely, the centrilobular zone III has the poorest oxygenation, and will be most affected during a time of ischemia.
Functionally, zone I hepatocytes are specialized for oxidative liver functions such as gluconeogenesis, β-oxidation of fatty acids and cholesterol synthesis, while zone III cells are more important for glycolysis, lipogenesis and cytochrome P-450-based drug detoxification. This specialization is reflected histologically; the detoxifying zone III cells have the highest concentration of CYP2E1 and thus are most sensitive to NAPQI production in acetaminophen toxicity. Other zonal injury patterns include zone I deposition of hemosiderin in hemochromatosis and zone II necrosis in yellow fever.
Pathology of Acute and Chronic Hepatitis:
The liver, like all organs, responds to injury in a limited number of ways and a number of patterns have been identified. Liver biopsies are rarely performed for acute hepatitis and because of this the histology of chronic hepatitis is better known than that of acute hepatitis.
Pathology of Acute Hepatitis
In acute hepatitis the lesions (areas of abnormal tissue) predominantly contain diffuse sinusoidal and portal mononuclear infiltrates (lymphocytes, plasma cells, Kupffer cells) and swollen hepatocytes. Eosinophilic cells (Councilman bodies) are common. Hepatocyte regeneration and cholestasis (canalicular bile plugs) typically are present. Bridging hepatic necrosis (areas of necrosis connecting two or more portal tracts) may also occur. There may be some lobular disarray. Although aggregates of lymphocytes in portal zones may occur, these are usually neither common nor prominent. The normal architecture is preserved. There is no evidence of fibrosis or cirrhosis (fibrosis plus regenerative nodules). In severe cases prominent hepatocellular necrosis around the central vein (zone 3) may be seen.
In submassive necrosis – a rare presentation of acute hepatitis – there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease.
Two distinct patterns of necrosis have been recognized: (1) zonal coagulative necrosis or (2) panlobular (nonzonal) necrosis. Numerous macrophages and lymphocytes are present. Necrosis and inflammation of the biliary tree occurs. Hyperplasia of the surviving biliary tract cells may be present. Stromal hemorrhage is common.
The histology may show some correlation with the cause:
- Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia.
- Zone 2 (midzonal) – rare – is seen in yellow fever.
- Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure or chloroform ingestion. Drugs such as acetaminophen may be metabolized in zone 1 to toxic compounds that cause necrosis in zone 3.
Where patients have recovered from this condition, biopsies commonly show multiacinar regenerative nodules (previously known as adenomatous hyperplasia).
Massive hepatic necrosis is also known and is usually rapidly fatal. The pathology resembles that of submassive necrosis but is more marked in both degree and extent.
Pathology of Chronic Hepatitis
Chronic hepatitis has been better studied and several conditions have been described.
Chronic hepatitis with piecemeal (periportal) necrosis (or interface hepatitis) with or without fibrosis (formerly chronic active hepatitis) is any case of hepatitis occurring for more than 6 months with portal based inflammation, fibrosis, disruption of the terminal plate, and piecemeal necrosis. This term has now been replaced by the diagnosis of 'chronic hepatitis'.
Chronic hepatitis without piecemeal necrosis (formerly called chronic persistent hepatitis) has no significant periportal necrosis or regeneration with a fairly dense mononuclear portal infiltrate. Councilman bodies are frequently seen within the lobule. Instead it includes persistent parenchymal focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal infiltrates.
The older terms have been deprecated because the conditions are now understood as being able to alter over time so that what might have been regarded as a relatively benign lesion could still progress to cirrhosis. The simpler term chronic hepatitis is now preferred in association with the causative agent (when known) and a grade based on the degree of inflammation, piecemeal or bridging necrosis (interface hepatitis), and the stage of fibrosis. Several grading systems have been proposed but none have been adopted universally.
Cirrhosis is a diffuse process characterized by regenerative nodules that are separated from one another by bands of fibrosis. It is the end stage for many chronic liver diseases. The pathophysiological process that results in cirrhosis is as follows: hepatocytes are lost through a gradual process of hepatocellular injury and inflammation. This injury stimulates a regenerative response in the remaining hepatocytes. The fibrotic scars limit the extent to which the normal architecture can be reestablished as the scars isolate groups of hepatocytes. This results in nodule formation. Angiogenesis (new vessel formation) accompanies scar production which results in the formation of abnormal channels between the central hepatic veins and the portal vessels. This in turn causes shunting of blood around the regenerating parenchyma. Normal vascular structures including the sinusoidal channels may be obliterated by fibrotic tissue leading to portal hypertension. The overall reduction in hepatocyte mass, in conjunction with the portal blood shunting, prevents the liver from accomplishing its usual functions – the filtering of blood from the gastrointestinal tract and serum protein production. These changes give rise to the clinical manifestations of cirrhosis.
Hepatic Pathology and Specific causes
Most of the causes of hepatitis cannot be distinguished on the basis of the pathology but some do have particular features that are suggestive of a particular diagnosis.
Alcohol: The presence of micronodular cirrhosis, Mallory bodies and fatty change within a single biopsy are highly suggestive of alcoholic injury. Perivenular, pericellular fibrosis (known as 'chicken wire fibrosis' because of its appearance on trichrome or Van Gieson's stains) with partial or complete obliteration of the central vein is also very suggestive of alcohol abuse.
Vascular: Cardiac, ischemic and venous outflow obstruction all cause similar patterns. The sinusoids are often dilated and filled with erythrocytes. The liver cell plates may be compressed. Coagulative necrosis of the hepatocytes can occur around the central vein. Hemosiderin and lipochrome laden macrophages and inflammatory cells may be found. At the edge of the fibrotic zone cholestasis may be present. The portal tracts are rarely significantly involved until late in the course.
Biliary tract disease including primary biliary cirrhosis, sclerosing cholangitis, inflammatory changes associated with idiopathic inflammatory bowel disease and duct obstruction have similar histology in their early stages. Although these diseases tend to primarily involve the biliary tract they may also be associated with chronic inflammation within the liver and difficult to distinguish on histological grounds alone. The fibrotic changes associated with these diseases principally involve the portal tracts with cholangiole proliferation, portal tract inflammation with neutrophils surrounding the cholangioles, disruption of the terminal plate by mononuclear inflammatory cells and occasional hepatocyte necrosis. The central veins are either not involved in the fibrotic process or become involved only late in the course of the disease. Consequently, the central–portal relationships are minimally distorted. Where cirrhosis is present it tends to be in the form of a portal–portal bridging fibrosis.
Hepatitis E causes different histological patterns that depend on the host's background. In immunocompetent patients the typical pattern is of severe intralobular necrosis and acute cholangitis in the portal tract with numerous neutrophils. This normally resolves without sequelae. Disease is more severe in those with preexisting liver disease such as cirrhosis. In the immunocompromised patients chronic infection may result with rapid progression to cirrhosis. The histology is similar to that found in hepatitis C virus with dense lymphocytic portal infiltrate, constant piecemeal necrosis and fibrosis.
Prognosis of Hepatitis
The outcome of hepatitis depends heavily on the disease or condition that is causing the symptoms. For some causes, such as subclinical Hepatitis A infection, the person may not experience any symptoms and will recover without any long-term effects. For other causes hepatitis can result in irreparable damage to the liver and require a liver transplant. A subset referred to in a 1993 classification as "hyperacute" liver failure can happen in less than a week.
The liver can regenerate damaged cells. Chronic damage to the liver can result in the formation of scar tissue called fibrosis and can result in nodules that block the liver from functioning properly; this condition is called cirrhosis and is not reversible. Cirrhosis may indicate a liver transplant is necessary. Another complication of chronic hepatitis is liver cancer, specifically hepatocellular carcinoma.
In March 2015 the World Health Organisation issued its first guidelines for the treatment of chronic hepatitis B. This condition is affecting some 240 million people worldwide. These guidelines are for the prevention, care and treatment of persons living with chronic hepatitis B.
Clinical Manifestations of Viral Hepatitis
Chronic Viral Hepatitis is a liver-centered viral infection that causes metabolic imbalances in those infected. These imbalances result in clinical manifestations of Hepatitis, which can be brought into balance (homeostasis) by the dietary administration of specific nutrients at specific levels. These clinical manifestations are:
- Hepatitis causes an increase in the production of free radical reactive oxygen species (ROS) in the mitochondria of cells. The resulting oxidative stress in the cytosol is clinically significant to the pathogenesis of Hepatitis as well as in the generation and progression of fibrosis in Hepatitis
- Hepatitis causes increased levels of inflammation in the cells of the liver. This inflammation is clinically significant to the pathogenesis of Hepatitis as well as in the progression of fibrosis in Hepatitis patients.
- Hepatitis causes oxidative damage to vulnerable cell membranes, including interior organelle membranes. This is manifested by changes in membrane phospholipid profiles, as well as changes in membrane function, fluidity, and integrity. Hepatitis genotype 3 contributes to steatosis, which is manifested by the abnormal retention of lipids inside the cells of the liver. Metabolic steatosis is identified as NAFLD/NASH. Steatosis, regardless of cause, is clinically significant in the pathogenesis of Hepatitis C as well as in the progression of fibrosis in Hepatitis patients.
- The combination of the above clinical manifestations of Hepatitis promotes the activation of the gene transcription factor NFkappaB. This activation starts a chain of events that leads the progression of fibrosis or cirrhosis in the liver. Specifically, NFkappaB activation triggers the production of pro-inflammatory peptides and proteins, the activation of stellate cells, their conversion to myofibroblasts, and the secretion and accumulation of collagen (scar tissue) in the spaces of the liver (fibrosis to cirrhosis).
- The HepTech Comprehensive Medical Food Protocol involves the administration of distinctive nutrients that Hepatitis patients require to ameliorate the clinical manifestations of Hepatitis. Amelioration of these specific clinical manifestations of Hepatitis C decreases levels of activation of the metabolic stimulus (NFkappaB) that triggers the generation and accumulation of scar tissue (fibrosis to cirrhosis) in the spaces of the liver.