Continuing Education Activity

The term hepatitis means inflammation of the liver — hepatitis most commonly results from viruses. But drugs, alcohol, toxins, and certain diseases, including autoimmune diseases, can also cause hepatitis. This article covers various causes of hepatitis, epidemiology, symptomatology, patient evaluation, treatment of the disease, prognosis, and preventive strategies. This activity highlights the role of healthcare teams in caring for patients who have hepatitis.

Objectives:

• Describe the etiology, epidemiology, pathophysiology of hepatitis.
• Summarize risk factors, patient history, and presentation with physical exam findings associated with hepatitis.
• Outline diagnostic tests, treatment considerations, common complications, prognosis, and preventive strategies in hepatitis.
• Review some interprofessional team strategies for improving care coordination and communication to advance and improve outcomes in hepatitis.

Introduction

Hepatitis is defined as inflammation of the liver that can result from a variety of causes such as heavy alcohol use, autoimmune, drugs, or toxins. However, the most frequent cause of hepatitis is due to a viral infection and is referred to as viral hepatitis. In the United States, the most common types of viral hepatitis are Hepatitis A, Hepatitis B, and Hepatitis C. The other types of viral hepatitis are hepatitis D and E and are less frequently encountered.[1]. Based on the etiology of hepatitis, the severity can range from mild and self-limiting to severe illness requiring liver transplantation. Hepatitis can be further classified into acute and chronic based on the duration of the inflammation/insult to the liver. If inflammation of the liver lasts for less than 6 months, then it is termed as acute hepatitis and if it lasts longer than 6 months it is termed as chronic hepatitis. Acute hepatitis is usually self-resolving but can cause fulminant liver failure depending on the etiology. In contrast, chronic hepatitis can cause liver damage that includes liver fibrosis, cirrhosis, hepatocellular carcinoma, and features of portal hypertension leading to significant morbidity and mortality[2][3].

Etiology

Viral Hepatitis

Most of the time, hepatitis results from hepatitis viruses A, B, C, D, and E. It is unclear whether the Hepatitis G virus is pathogenic in humans or not. Hepatitis A, B, C, and D are endemic to the United States with hepatitis A, B, and C viruses causing 90% of acute viral hepatitis in the United States and Hepatitis C being the most common cause of chronic hepatitis.

Hepatitis A is an RNA virus from the Picornaviridae family. It is usually present in the highest concentration in the stool of infected individuals with the greatest viral load shedding occurring during the end of the incubation period. The most common mode of transmission of hepatitis A is via the fecal-oral route from contact with food, water, or objects contaminated by fecal matter from an infected individual. It is more commonly encountered in developing countries where due to poverty and lack of sanitation, there is a higher chance of fecal-oral spread. International travel is the most significant risk factor identified from the cases reported in the United States. People who come in contact with infected individuals are also at risk, and the secondary infection rate for household contacts is about 20%, which may also play a more prominent role in the maintenance of hepatitis A virus outbreaks[4].

Hepatitis B

Hepatitis B virus is a DNA virus and is a member of the Hepadnaviridae family. The composition of the viral core is nucleocapsid, hepatitis B core antigen (HBcAg), which surrounds hepatitis B virus DNA, and DNA polymerase. The nucleocapsid is coated with the hepatitis B surface antigen (HBsAg), which is a viral surface polypeptide. The gene that codes for hepatitis B core antigen (HBcAg), also codes for hepatitis B e antigen (HBeAg). Intact hepatitis B virus virion is known as the Dane particle. Hepatitis B virus is known to have eight genotype variants but is not used in clinical practice to determine the severity of the infection. Hepatitis B virus can be detected in serum, semen, vaginal mucus, saliva, and tears even at a lower level but not found in the stool, urine, or sweat. In the United States, estimates are about 2.2 million people have chronic hepatitis B virus infection. It is transmitted parenterally and sexually when individuals come in contact with mucous membranes or body fluids of infected individuals. Transfusion of blood and blood products, injection drug use with shared needles, needlesticks, or wounds caused by other instruments in healthcare workers and hemodialysis are all examples of parenteral and percutaneous exposures, but parenteral mode remains the dominant mode of transmission both globally and in the United States. Intravenous drug users, men who have sex with men, healthcare workers with exposure to infected body fluids, patients who require frequent and multiple blood transfusions, people who have multiple sexual partners, prisoners, partners of hepatitis B virus carriers, and persons born in endemic areas are all at high risk for hepatitis B virus infection. The virus can be transmitted perinatally also, and it occurs in infants of HBeAg positive women where the infants would have a 70% to 90% chance of infection, and 90% of those who become infected end up developing a chronic infection with hepatitis B virus [5].

Hepatitis C

Hepatitis C virus is an RNA virus and is a member of the Flaviviridae family with one serotype, but at least six major genotypes and more than 80 subtypes. The extensive genetic variability makes it challenging to develop a vaccine to prevent hepatitis C virus infection. Transmission can be parenteral, perinatal, and sexual, with the most common mode being the sharing of contaminated needles among IV drug users. Also, other high-risk groups include people who require frequent blood transfusions and organ transplantation of organs from infected donors. Sexual and perinatal transmission is not very common [6].

Hepatitis D

Hepatitis D is an RNA virus and a single species in the Deltavirus genus. It contains the hepatitis D antigen and RNA strand and used HBsAg as its envelope protein; therefore, those who get hepatitis D virus infection have coinfection with the hepatitis B virus as well. Hepatitis D virus has similar modes of transmission as the hepatitis B virus, but perinatal transmission is uncommon [7].

Hepatitis E

Hepatitis E is an RNA virus and a single species in the Hepevirus genus. The primary mode of transmission is the fecal-oral route. Fecally contaminated water is the most common means, but person-to-person transmission is rare. However, occasionally maternal-neonatal transmission can occur as well[8].

Hepatitis G

Hepatitis G virus is an RNA virus and is a member of the Pegivirus A species of the Flaviviridae family. The primary mode of transmission is through infected blood and blood products. It is usually a coinfection in people who have chronic hepatitis B or hepatitis C infections. It is associated with acute and chronic liver disease, but research has not clearly established it as an agent that causes hepatitis by itself [9].

Other less common causes of hepatitis are viruses like cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and Varicella-zoster virus, but these viruses do not target the liver primarily. 

Autoimmune Hepatitis

The exact etiology of autoimmune hepatitis is unknown. Various factors like drugs, environmental agents, or viral infection with hepatitis viruses or Epstein-Barr virus may trigger an autoimmune response. Patients develop autoantibodies, and they more commonly present in those who have chronic hepatitis C virus infection. Drugs like nitrofurantoin, minocycline, adalimumab, infliximab, or methyldopa can trigger autoimmune hepatitis. In these cases, hepatitis improves when the patient stops the offending drug [10].

Alcoholic Hepatitis

The exact mechanism of how alcoholic hepatitis is not well defined; many factors play a role that includes genetic factors, metabolism of ethanol and its metabolite acetaldehyde causing damage to hepatocyte cell membranes, malnutrition, immunologic factors such as stimulation of cytokines accelerating cell death, steatotic changes, free radicals, and oxidative injuries, etc. All these factors are known to play a role in causing alcoholic hepatitis [11]. 

Epidemiology

Viral Hepatitis

Viral Hepatitis is considered a major public health issue. Viral hepatitis infects millions of people annually causing significant morbidity and mortality. Chronic Hepatitis B and C infection can cause liver damage that includes liver fibrosis, cirrhosis, hepatocellular carcinoma, and features of portal hypertension. The World Health Organization (WHO) estimated that 1.3 million people have died due to hepatitis in 2015, and 1 in 3 people in the world have had infections with either hepatitis B or hepatitis C virus. Reportedly, infection rates show that 2 billion people infected with the hepatitis B virus, 185 million with the hepatitis C virus, and 20 million with the hepatitis E virus [12][13][14]. Hepatitis A virus affects 90% of children in high endemic regions [15]. Viral hepatitis ends up causing 1.4 million deaths annually, and hepatitis B and C viruses are responsible for about 90% of those deaths.

Hepatitis A

Typically, people who have access to safe drinking water and regions with stronger socioeconomic levels have very low levels of hepatitis A virus infection with less than 50% of the population being endemic while people who do not have access to safe drinking water & regions with low-income have high levels of hepatitis A virus infection with more than 90% of the population being endemic.[16] The infection rate is much higher worldwide for Hepatitis A, but only 1.5 million cases are reported annually. Children who get infected at an early age with asymptomatic exposure end up acquiring lifelong immunity in highly endemic countries[17].In the US, approximately 24,900 new infections are diagnosed each year

Hepatitis B

Estimates are that about one-third of the World's population has had an infection with hepatitis B, and around 5% of this population remain carriers of hepatitis B. About 25% of these carries develop chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The documented number of global deaths annually from hepatitis B virus infection is 780000. [18][19].In the US approximately 22,600 new infections were diagnosed in 2018 and it is estimated that 862,000 people have chronic Hepatitis B infection.

Hepatitis C

Hepatitis C virus is the most prevalent cause of parenteral hepatitis worldwide. It is prevalent in the 0.5% to 2% population around the world, with most commonly being affected are IV drug users and hemophiliacs. However, with the advent of safer screening and viral elimination techniques for blood transfusion, the incidence of transfusion-associated hepatitis C virus infection is going down. Approximately 71 million people globally have chronic hepatitis C infection, and this accounts for close to 400000 deaths every year[20][21].In the US approximately 50,300 new infections were diagnosed in 2018 and it is estimated that 2.4 million people have chronic Hepatitis C infection.

Hepatitis D    

Hepatitis D occurs in patients who are positive for HBsAg, and hepatitis D either occurs as a coinfection with Hepatitis B or patients who are chronic Hepatitis B virus carries can get superinfection with hepatitis D virus. Hepatitis D is not a reportable disease in the USA; therefore, accurate data is not available, but it is estimated to affect 4% to 8% of cases of acute hepatitis B and 5% of global chronic hepatitis B patients. Approximately 18 million patients are infected with the hepatitis D virus globally. Prevalence remains high in South America and Africa as well prevalence also remains high in sex workers in Greece and Taiwan, where it has been well studied.[22]  

Hepatitis E    

Hepatitis E virus is associated with worldwide outbreaks of food and waterborne diseases and commonly seen in developing countries with restricted access to sanitation, clean water, and poor hygiene. About 20 million people are estimated to be infected with the hepatitis E virus globally, and there have been approximately 44000 deaths due to hepatitis E virus infection. In that regard, the hepatitis E virus carries a higher risk of mortality at about 3.3% compared to hepatitis A virus infection despite a similar route of transmission and lack of chronicity.[23]  

Hepatitis G

Global infection with the hepatitis G virus is common, and the virus is detectable in all ethnicities.  The worldwide prevalence of hepatitis G is around 3%, and researchers believe that 1 to 4% of blood donors worldwide are carriers of the virus.  The belief is that around 25% of the global population carries an antibody to the virus.  Infected blood products increase the prevalence of hepatitis G virus, and persistent infection is a present insignificant number of healthy blood donors, and 35% of the patients had HIV infection; however, donor blood is not tested for hepatitis G. Reports indicate that about 10% to 20% of adults with chronic HBV or HCV infection have hepatitis G infection, indicating that coinfection is a common occurrence. Still, it does not increase the severity of the disease. There is some suspicion for sexual transmission of hepatitis C as high detection rates exist in men who have sex with men and professional sex workers.  Vertical transmission of the hepatitis G virus from an infected mother to the newborn has also been documented, but it is very rare.[24]

Autoimmune Hepatitis  

The prevalence of autoimmune hepatitis is estimated to be 0.1 to 1.2 cases per 100000 people in Western Europe. Autoimmune hepatitis accounts for about 6% of liver transplantation in the United States, while it accounts for about 3% of liver transplantations in Europe. Prevalence in Japan is estimated to be 0.08 to 0.015 cases per 100000 persons and causes 1.9% of cases of liver cirrhosis.[25]   

Alcoholic Hepatitis

The precise prevalence of alcoholic hepatitis is unknown, but it is known to be high, with a rising rate of mortality. It is difficult to assess the correct prevalence as alcoholic hepatitis may remain undiagnosed and completely asymptomatic. The prevalence of alcohol use disorder is about 8% of the population of the United States or 16 million people. However, approximately 35% of those with the diagnosis have changes consistent with alcoholic hepatitis, which means that around 5 million patients may have alcoholic hepatitis.[26]

Pathophysiology

Viral Hepatitis

Hepatitis A

The incubation period of hepatitis A virus is approximately four weeks. Acute infections of hepatitis A virus are more severe with higher mortality in adults than children. Symptoms include malaise, anorexia, nausea, vomiting, and jaundice. Relapses are not common, and the infection does not result in chronic hepatitis. Also, only less than 1% of cases result in fulminant hepatic failure.[27]

Hepatitis B

The incubation period of an acute hepatitis B virus infection is approximately 12 weeks, with a majority of patients experiencing mild illness and less than 1% experiencing fulminant hepatic failure. After acute infection resolves, the majority of adult patients and a small percentage of infected infants develop antibodies against the hepatitis B surface antigen and end up recovering fully. However, a small percentage of adult patients and the majority of infected infants end up developing chronic infection. About 10% to 30% of carriers become symptomatic from chronic infection. They can also have extrahepatic manifestations of the disease. About 20% of chronic hepatitis patients end up developing cirrhosis and hepatic decompensation, while 5% end up developing hepatocellular carcinoma.[28]

Hepatitis C

The incubation period of hepatitis C virus is approximately eight weeks. Most cases of acute hepatitis C infection are asymptomatic; however, about 55% to 85% of patients develop chronic hepatitis C and liver disease, and 30% of those patients end up developing cirrhosis.  Patients who are infected with the hepatitis C virus and have a chronic infection are at high risk of developing hepatocellular carcinoma. Close to 20,000 deaths annually are attributable to chronic hepatitis C infection as a contributing cause of death.[29]  

Hepatitis D  

The incubation period for hepatitis D virus is approximately 13 weeks. Hepatitis D virus infection causes hepatitis only in persons with acute or chronic hepatitis B virus infection. Symptoms are similar to acute hepatitis B virus infection, but patients with chronic hepatitis B virus infection and hepatitis D virus infection tend to progress more rapidly to cirrhosis than those patients with chronic hepatitis B virus infection alone. Also, patients already infected with the hepatitis B virus may develop superinfection if also infected with the hepatitis D virus.  Superinfection can result in fulminant hepatic failure.[22]  

Hepatitis E

The incubation period for hepatitis E virus is approximately 2 to 10 weeks.  Acute hepatitis E virus infection is less severe compared to acute hepatitis B virus infection, but pregnant females infected in the third trimester have a greater than 25% mortality associated with hepatitis E infection.[30]  

Hepatitis G

The incubation period of hepatitis G is approximately 14 to 20 days. The clinical picture can be similar to the picture of mild hepatitis infection with other hepatitis viruses, and patients can have normal or low aminotransferase without jaundice. The elevation of alanine aminotransferase (ALT) is not proportional to the degree of viremia in hepatitis G, unlike hepatitis C, where patients with high viral load can have a higher alanine aminotransferase (ALT) levels.[24]

Autoimmune Hepatitis  

Autoimmune hepatitis typically results in high levels of gammaglobulin and circulating autoantibodies. Many patients have a family history of other autoimmune disorders or have responded in the past to immunosuppressive therapy. The pathogenetic mechanism is not entirely understood, but studies have shown that patients who develop autoimmune hepatitis sometimes have a genetic predisposition to the disease in susceptible individuals, who may develop the disease secondary to a viral infection or an idiosyncratic reaction to the drug, which can act as an inducing mechanism.[31]  

Alcoholic Hepatitis    

The pathogenetic mechanism of alcoholic hepatitis is complex and multifactorial.  It results from interactions between ethanol metabolism, inflammation, and innate immunity, which end up causing hepatocyte death by necrosis or apoptosis from oxidative stress.  Studies have shown cytokines and tumor necrosis factors playing a role also in causing hepatotoxicity.[11]

History and Physical

Clinical Presentation

Viral Hepatitis 

Clinical presentation of viral hepatitis can be different in every individual depending on the type of virus causing the infection. Patients can be entirely asymptomatic or only mildly symptomatic at presentation. A small number of patients can present with rapid onset of fulminant hepatic failure.

Typically patients with viral hepatitis go through 4 phases.

Phase 1 (viral replication phase) - Patients are usually asymptomatic in this phase, and laboratory studies are positive for markers of hepatitis.

Phase 2 (prodromal phase) - Patients in this phase usually present with anorexia, nausea, vomiting, malaise, pruritus, urticaria, arthralgias, and fatigue. Many times these patients are misdiagnosed as having gastroenteritis or viral infection.

Phase 3 (icteric phase) - Patients in this phase present with dark-colored urine and pale-colored stool. Some patients develop jaundice and right upper quadrant pain with liver enlargement.

Phase 4 (convalescent phase) - Patients typically start noticing the resolution of symptoms, and laboratory studies show liver enzymes returning to normal levels.[32]

Hepatitis A

Patients who are infected with hepatitis A virus usually present with symptoms similar to gastroenteritis or viral respiratory infection, including symptoms of fatigue, nausea, vomiting, fever, jaundice, anorexia, and dark urine. Symptoms usually start after the incubation period is over, and they resolve spontaneously in a majority of patients [4].

Hepatitis B

Patients with hepatitis B virus infection enter the prodromal phase after the incubation period and have symptoms of anorexia, malaise, and fatigue which are the most common initial clinical symptoms.  Some patients may experience right upper quadrant pain due to hepatic inflammation.  A small percentage of patients experience fever, arthralgias, or rash.  Once these patients progress to the icteric phase, they develop jaundice and painful hepatomegaly.  dark-colored urine and pale-colored stools. After the icteric phase, clinical course can be variable where some patients experience rapid improvement in the symptoms, and others can develop a prolonged illness with a slow resolution with periodic flareups.  A small number of patients can have rapid progression of the disease that can lead to fulminant hepatic failure over a few days to weeks [32].

Hepatitis C

Patients infected with the hepatitis C virus develop similar symptoms after the incubation period to those of hepatitis B virus infection during the acute infection phase with symptoms of anorexia, malaise, and fatigue.  However, 80% of patients remain asymptomatic and do not develop jaundice [6].

Hepatitis D

The majority of patients who have a simultaneous infection with the hepatitis B virus and hepatitis D virus have a self-limited infection.  Symptoms are similar to acute hepatitis B infection. Chronic hepatitis B virus carriers who develop superinfection with hepatitis D virus tend to have more severe acute hepatitis, and the majority of these patients end up developing chronic hepatitis D virus infection. Chronic infection with both hepatitis B virus and hepatitis D virus can lead to fulminant liver failure, severe chronic active hepatitis, and progression to cirrhosis in a majority of patients compared to those patients who only have chronic hepatitis B virus infection [33].

Hepatitis E

Patients with acute hepatitis E virus infection develop an acute self-limited illness similar to hepatitis A virus infection. Fulminant hepatic failure is rare, but patients with hepatitis E infection who are pregnant have a higher mortality rate.[34]

Hepatitis G

Patients with hepatitis G infection can have a mild infection without jaundice, but most patients are asymptomatic. There have been few reports of fulminant and chronic hepatitis as well as hepatic fibrosis also, but it is not common. The patient can have an elevation of alkaline phosphatase and gamma-glutamyl transpeptidase as well, but most patients infected with the hepatitis G virus have normal liver function tests [24].

Autoimmune Hepatitis

Autoimmune hepatitis can clinically present in various ways. Patients can be completely asymptomatic, with the only abnormality being the elevation of liver enzymes on the laboratory studies compared to those presenting with fulminant hepatitis. Symptoms depend on the stage of the liver disease at the time of presentation.  The most common symptoms include fatigue, malaise, jaundice, abdominal pain, and arthralgias.  In the late stages, patients can have ascites, hepatic encephalopathy, and variceal bleed.  Patients can also have other autoimmune diseases along with autoimmune hepatitis and can experience symptoms from those diseases as well [35].

Alcoholic Hepatitis

Patients with alcoholic hepatitis usually are malnourished and have physical signs of hepatomegaly and splenomegaly. Fever and tachycardia, along with right upper quadrant pain, have been reported as well.  Hepatic bruit due to an increase in the blood flow is characteristic of alcoholic hepatitis but is not a common finding. Other symptoms can include nausea, vomiting, malaise, and anorexia. More severe cases can have hepatic encephalopathy, hepatorenal syndrome, ascites, and variceal bleed due to portal hypertension, coagulopathy, and thrombocytopenia.[36].

Physical Examination

Physical findings vary in individual patients depending on the time of presentation. Many times patients present with a low-grade fever. Patients can show signs of dehydration, especially if they have been having vomiting and loss of appetite. Findings like a dry mucous membrane, tachycardia, delayed capillary refill, etc. can be observed. During the icteric phase, patients can have jaundiced skin or sclerae and sometimes can have urticarial rashes. Tender hepatomegaly may be observed. In advanced liver failure, signs of ascites, pedal edema, malnourishment may be observed. In alcoholic hepatitis, patients may have splenomegaly along with hepatomegaly.[37]

Evaluation

Baseline evaluation in a patient suspected to have viral hepatitis can be started by checking a hepatic function panel. Patients who have a severe disease can have elevated total bilirubin levels. Typically, levels of alkaline phosphatase (ALP) remain in the reference range, but if it is elevated significantly, the clinician should consider biliary obstruction or liver abscess. In advanced liver disease, prothrombin time (PT) and international normalized ratio (INR) may appear prolonged. Patients may also have leukopenia and thrombocytopenia. Patients who suffer from easy bruising, variceal bleed, or hemorrhoidal bleed due to advanced liver disease may have anemia with low hemoglobin and hematocrit levels. Blood urea nitrogen (BUN) and serum creatinine levels are also necessary for patients suspected to have advanced liver disease to look for renal impairment. Patients who present with altered mental status should have serum ammonia levels checked and are usually elevated in the presence of hepatic encephalopathy[38].

Besides these routine laboratory tests, other specific tests are available to evaluate for the type of viral hepatitis. 

Viral Hepatitis

Hepatitis A

The standard test for diagnosing acute infection with hepatitis A virus is the presence of immunoglobulin M (IgM) antibody to the hepatitis A virus.  IgM antibody disappears a few months after the acute infection.  In the later stages of infection, immunoglobulin G (IgG) antibody to hepatitis A virus is detected. However, the presence of IgG antibody to hepatitis A virus only means that the patient has been infected with hepatitis A virus in the past, from 2 months to several decades ago.  IgG antibody to hepatitis A virus does not mean acute infection and most patients who have IgG antibody to hepatitis A virus have lifelong immunity against hepatitis A virus infection [27].

Hepatitis B

Work-up for hepatitis B virus infection divides into work-up for acute infection and chronic infection.

Acute Infection

In patients who have an acute hepatitis B virus infection, the first serum marker to appear is the hepatitis B surface antigen (HBsAg).  This antigen means that patients have the hepatitis B virus in the blood, but it does not indicate an acute or chronic infection in the absence of symptoms.  When the patient shows symptoms of acute hepatitis, the presence of HBsAg strongly suggests acute hepatitis B virus infection, but it also does not rule out chronic hepatitis B infection with an acute superinfection by another type of hepatitis virus. HBsAg disappears in about six months after the acute infection in those patients who clear the hepatitis B virus, but if it remains present longer than six months, it indicates chronic infection. Patients who end up clearing HBsAg from the blood, the antibody to HBsAg (anti-Hbs) appear.  This antibody may persist for a lifetime and is believed to offer immunity to the patients from subsequent exposure to the hepatitis B virus.

The first antibody to appear is the immunoglobulin M (IgM) antibody to hepatitis B core antigen (HBcAg).  The presence of IgM anti-HBc also means that patients have an acute hepatitis B virus infection and is required to make the diagnosis.  Once the IgM anti-HBc disappears in a few weeks, IgG anti-HBc is detected, which usually remains present for life.  Total assay for antibody to hepatitis B core antigen (anti-HBc) can detect both IgM and IgG antibodies and indicates that patients have a history of infection with hepatitis B virus at some point of time in the past as it remains positive both in patients who clear the virus and those who have a persistent infection.

Hepatitis B e antigen (HBeAg) is also present and indicates that the virus is replicating. After the viral replication slows down, HBeAg disappears in the blood, and antibody to HBeAg (anti-HBe) appears, which can persist in the blood for a long time. 

Chronic Infection

Patients who have chronic hepatitis B infection can have positive HBsAg for life.  These patients can be inactive carriers of the hepatitis B virus or may have active chronic hepatitis. All patients with chronic hepatitis B virus infection have the presence of anti-HBc. If HBeAg may or may not be present, but if it present in patients with active chronic hepatitis, it can indicate viral replication. Similarly, hepatitis B virus DNA may or may not be present, but high levels indicate active chronic hepatitis. Patients with chronic infection of hepatitis B usually have an absence of anti-HBs, but the presence of anti-HBs with positive HBsAg in patients with chronic infection with the hepatitis B virus means that the antibody was unsuccessful in inducing the viral clearance.

Evaluation of hepatitis B virus infection can be complicated, and some uncommon but possible scenarios should be kept in mind while investigating. Patients can test negative for HBsAg and anti-HBs but can have the presence of anti-HBc. This situation is possible when the result is false positive but can also happen in patients who are in the time window where they have cleared HBsAg from the blood, but anti-HBs has not yet appeared. Some patients who have cleared hepatitis B virus infection but have lost the anti-HBs over the years can test negative both for HBsAg and anti-HBs but positive for anti-HBc.  Also, patients infected with the hepatitis B virus many years ago can sometimes develop a core mutant variant of the hepatitis B virus where they can test negative for HBeAg and positive for anti-HBe even though the virus may still be active and is replicating. When lab findings like these are detected, the hepatitis B virus DNA PCR assay to check for viral replication is recommended. 

Patients who receive a vaccine for the hepatitis B virus develop protective anti-HBs as a response to recombinant HBsAg in the vaccine.  There are no hepatitis B virus DNA or other hepatitis B virus-associated proteins in the vaccine.  Patients who receive the vaccine are not positive for anti-HBc unless they had a previous infection with the hepatitis B virus.[39]

Hepatitis C

Hepatitis C virus infection can be confirmed with antibody to hepatitis C virus (anti-HCV).  These assays can detect antibodies within 4 to 10 weeks of infection and are pretty sensitive and specific.  Anti-HCV can remain negative for a few months after an acute hepatitis C virus infection, but once it appears in the blood, it remains present for life.  However, it is important to remember that anti-HCV is not a protective antibody, unlike anti-HBs, and does not offer protection from subsequent exposure to the hepatitis C virus. After patients have positive hepatitis C serology, hepatitis C virus RNA testing can provide confirmation. It is the most specific test for hepatitis C virus infection and can detect acute infection even before antibodies develop. It is also helpful in confirming false-positive cases, seronegative cases, and cases where perinatal transmission has taken place. It can also provide information on viral load, hepatitis C virus genotype, predict response to interferon treatment, which can help healthcare providers to determine the duration and dose of the interferon as well as assess the likelihood of relapse after the treatment.

Liver biopsy is an important diagnostic test especially in patients with chronic hepatitis C and can help with confirmation of the diagnosis, exclude other diseases, and allow reliable assessment of the severity of the disease, including the severity of hepatic fibrosis.  Knowledge of the degree of hepatic fibrosis can help healthcare providers to make decisions regarding whether to initiate antiviral therapy or not. However, liver biopsy is an invasive procedure and can cause complications like infection and bleeding.  Also, in some patients, the damage to the liver is not uniform, and therefore, sampling error can occur. The liver biopsy also cannot be used to predict the rate of progression in patients with chronic hepatitis C infection. Some newer blood tests can be used to determine the degree of hepatic fibrosis but are no substitute for liver biopsy as of yet due to the lower accuracy.  Vibration-controlled transient elastography, which received approval in 2013 in the United States, can help diagnose cirrhosis in a majority of patients but is less accurate in patients with a lesser degree of fibrosis and therefore is not used as a substitute for the liver biopsy.

Other infrequently used test includes liver function testing that can indicate the presence of liver injury but is not very accurate in predicting the severity of the disease. Liver function testing can be more valuable in monitoring therapeutic response to the hepatitis C treatment with improvement in aminotransferase levels indicating patients responding to the treatment while worsening of aminotransferase levels post hepatitis C treatment may indicate a relapse. However, these days it is not in common use as HCV RNA has become a test of choice for healthcare providers to monitor the response.[40][41]

Hepatitis D

Hepatitis D virus infection is diagnosed by checking for immunoglobulin M (IgM) and immunoglobulin G IgG) antibody to the hepatitis D virus (anti-HDV). IgM antibody to hepatitis B core antigen (anti-HBc) must be checked to differentiate a coinfection where the patients test positive for IgM anti-HBc and superinfection, where the patients test negative for IgM anti-HBc. Hepatitis D virus RNA test can be done but is not routinely performed.[42]

Hepatitis E

Hepatitis E virus infection is diagnosed by checking for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody to the hepatitis E virus (anti-HEV). Also, hepatitis E virus RNA can be checked in the serum and stool of infected patients.[43]

Hepatitis G

Hepatitis G virus is usually identified by checking the hepatitis G RNA PCR.  Most patients develop antibodies, which is detectable after the clearance of the virus. The coexistence of hepatitis G RNA and antibody to hepatitis G is not common.  Following the clearing of the virus is cleared and the antibody appears, patients make a full recovery, but patients who have persistent hepatitis G RNA can also have no biochemical or histological signs of liver disease; however, a small percentage of patients with chronic hepatitis G go on developing liver fibrosis.[9]

Autoimmune Hepatitis 

Autoimmune hepatitis should always be considered in the differential when evaluating patients with acute hepatitis. Work-up usually starts with getting serologic workup that includes serum antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), serum protein electrophoresis (SPEP), liver-kidney microsomal type 1 antibody (LKM-1), anti-liver cytosol 1 antibody (anti-LC1), antibody to soluble liver antigen (anti-SLA), perinuclear antineutrophil cytoplasmic antibody (pANCA) and quantitative immunoglobulins.  Patients can have significantly elevated aminotransferase levels along with elevated serum immunoglobulin levels, especially Ig G predominant gamma globulin levels. They can be seropositive for any of the antibodies mentioned above. Hypergammaglobulinemia is a frequent finding, and patients who have acute hepatitis without hypergammaglobulinemia are unlikely to have autoimmune hepatitis. Levels of gamma globulin or IgG can help monitor the response to therapy. Aminotransferase levels are not very accurate in predicting disease severity or response to therapy but are useful as an adjunct with other tests. 

Other values that require monitoring are serum bilirubin and alkaline phosphatase, which can be mild to moderately elevated in a majority of patients; however, a sharp increase in alkaline phosphatase can indicate the development of primary sclerosing cholangitis or onset of hepatocellular carcinoma especially in those patients who have advanced liver disease. Patients with autoimmune hepatitis may also have an elevated prothrombin time (PT), hypoalbuminemia, leukopenia, normochromic anemia, thrombocytopenia, and elevated erythrocyte sedimentation rate (ESR).

Liver biopsy is the gold standard diagnostic test in patients of autoimmune hepatitis. It can not only help determine the severity of the disease, but histopathologic findings on liver biopsy can also help differentiate it from chronic hepatitis C infection, alcoholic hepatitis, drug-induced liver injury, primary biliary cirrhosis, or primary sclerosing cholangitis.[44]

Alcoholic Hepatitis

If patients present with a history of alcohol abuse, typical signs, and symptoms of long-term alcohol abuse, and evidence of liver dysfunction, then usually no further diagnostic workup is required.  If the history is not clear or if patients do not have signs or symptoms of long-term alcohol abuse, then a complete blood count and metabolic panel along with liver function studies can be ordered.  Patients can have moderate anemia with an increase in the mean corpuscular volume (MCV) due to alcohol being a direct bone marrow suppressant.  Patients can also have some degree of leukocytosis with increased neutrophils. The metabolic panel can show hypokalemia and hypomagnesemia due to the effects of malnutrition and vomiting. C-reactive protein can be elevated and has an excellent positive predictive value. Liver enzymes have a characteristic pattern with aspartate aminotransferase (AST) being moderately elevated and alanine aminotransferase (ALT) being either in the reference range or only mildly elevated with the ratio of AST and ALT being greater than 1.  However, the AST/ALT ratio is greater than 1 in patients who have liver cirrhosis of any etiology. Therefore, it is not diagnostic of alcoholic hepatitis in patients with advanced liver disease. Alkaline phosphatase (ALP) is usually only mildly elevated. Gamma-glutamyl transpeptidase (GGTP) is elevated in patients with a history of alcohol use but is not diagnostic of alcoholic hepatitis. Liver biopsy is usually not required but remains a valuable diagnostic option to establish the diagnosis in patients with diagnostic uncertainty and for evaluating the severity of the disease.[45]

Apart from the investigations mentioned above, the clinician should consider uncommon and rare causes of hepatitis while making a diagnosis. If necessary, workup should pursue those causes. For example, iron, ferritin, and transferrin levels should be checked if hereditary hemochromatosis is suspected. Drug and toxin-induced liver disease should also be considered, and a careful and detailed history should be obtained. Imaging studies like ultrasonography, CT scan, and MRI also play an essential role in the work-up of hepatitis.

Treatment / Management

Viral Hepatitis

The basic treatment of acute viral hepatitis is supportive.  Patients who are experiencing significant nausea or vomiting and those who are elderly and immunocompromised should be admitted and started on intravenous fluids to rehydrate them. Patients who have complications like liver abscess, variceal bleed, or hepatic encephalopathy require admission and appropriate treatment. However, most of the patients can be safely monitored as an outpatient. Patients should avoid medications like acetaminophen or substances like alcohol that can be hepatotoxic.  Patients with acute viral hepatitis infection take proper rest and avoid vigorous physical activities until the symptoms improve. If required, patients should obtain a referral to specialty services like gastroenterology or hepatology.

Hepatitis A

Treatment for acute hepatitis A infection is supportive. There is no antiviral therapy for hepatitis A infection. Patients who have intractable nausea or vomiting, as well as those who are showing signs of liver failure, should be admitted and closely monitored.[4]

Hepatitis B

Treatment of hepatitis B virus infection falls into two categories, treatment of an acute HBV infection and chronic HBV infection.

Acute Hepatitis B Infection

Treatment of acute hepatitis B virus infection is supportive and similar to the treatment of acute hepatitis A infection. For severe cases of acute hepatitis B virus infection, lamivudine has been used and showed good results.[46]

Chronic Hepatitis B Infection

The main goal of treatment for chronic hepatitis B virus infection is the inhibition of viral replication with secondary goals being reducing symptoms and prevent or delay the progression of chronic hepatitis to cirrhosis or hepatocellular carcinoma. Inhibition of viral replication is indicated by loss of hepatitis B e antigen (HBeAg) and suppression of hepatitis B virus DNA levels. First-line monotherapy agents include pegylated interferon alfa-2a (PEG-IFN) and oral nucleoside or nucleotide analogs, including tenofovir or entecavir. Therapy should be selected based on individual patient profile, patient or provider preference, safety, efficacy, and cost of the treatment and risks of drug resistance. 

Pegylated interferon (PEG-IFN) treatment usually continues for 48 weeks for both HBeAg positive and negative chronic hepatitis. Advantages of pegylated interferon (PEG-IFN) treatment include high rates of seroconversion within one year of therapy and absence of resistance however it has many side effects including flu-like symptoms, fatigue, weight loss, depression, fatigue, loss of appetite, nausea, bone marrow suppression, etc. and is not well-tolerated. Also, patients require weekly injections, and with many side effects, compliance remains a big issue.  Pegylated interferon (PEG-IFN) treatment is contraindicated in patients who have suicidal tendencies, psychiatric disorder, autoimmune conditions, pregnancy, decompensated cirrhosis, and blood dyscrasias.

Treatment with oral agents like tenofovir or entecavir usually continues for 1 to 2 years; however, almost all patients require indefinite therapy as withdrawal of treatment usually results in relapse. The advantages of treating with tenofovir or entecavir include ease of administration and infrequent side effects as these drugs have an excellent safety profile and are well-tolerated.  Tenofovir is contraindicated in children and can cause renal insufficiency, decreased bone density, Fanconi syndrome, and proximal tubular acidosis; however, these side effects are rare. Patients with renal insufficiency should have their tenofovir dose adjusted. Entecavir should be used cautiously in patients with decompensated liver disease and renal insufficiency and can cause headaches, cough, fatigue, and abdominal pain, but the side effects usually remain mild. Patients who cannot receive pegylated interferon (PEG-IFN) treatment usually tolerate these oral agents well. These agents have a very potent antiviral effect with viral suppression seen in more than 95% of patients over five years with the prevention of cirrhosis and fibrosis regression.  However, due to its indefinite duration of therapy, more studies are required to evaluate long-term safety and risk of drug resistance. Effectiveness of combination therapy with two oral agents or one oral agent with pegylated interferon (PEG-IFN) is not well established and is currently being studied.[47]

Hepatitis C

Treatment of hepatitis C virus infection divides into two categories, treatment of an acute HCV infection and chronic HCV infection.

Acute Hepatitis C Infection

Acute hepatitis C infection is usually not detected frequently, but when detected, early interferon therapy is an option. Data regarding the efficacy of early interferon therapy is limited, but some studies have shown a sustained virologic response as in chronic hepatitis C virus infection treatment, which is defined as an undetectable serum hepatitis C virus RNA 6 months after completion of treatment. It must be kept in mind, however, that the patients in whom acute hepatitis C virus infection is detected may still be able to eliminate the infection spontaneously. Therefore, the antiviral therapy may be started six months after the hepatitis C virus infection is diagnosed depending on case by case basis except in cases of acute HCV infection after liver transplantation where the antiviral therapy should start immediately.[48]

Chronic Hepatitis C Infection

The main goal of treatment for chronic hepatitis C virus infection is the eradication of the hepatitis C virus, with secondary goals being reducing symptoms, prevent or delay the progression of chronic hepatitis to cirrhosis or hepatocellular carcinoma, and treat extrahepatic complications of the hepatitis C virus infection like glomerulonephritis and cryoglobulinemia. Pegylated interferon alfa-2b and alfa-2a have been the drug of choice for more than two decades and are used along with ribavirin as a combination therapy. This combination therapy is usually given for a duration of 24 weeks to 48 weeks, depending on the genotype of the hepatitis C virus. Treatment with pegylated interferon (PEG-IFN) has shown sustained virologic response with the eradication of hepatitis C virus RNA and a reduction in the rate of fibrosis progression. Therapy should be selected based on individual patient profile, patient or provider preference, safety, efficacy, and cost of the treatment and risks of drug resistance. Patients must understand in advance that eradication of the hepatitis C virus can not be achieved in every case and may not always be necessary to achieve the desired clinical result.  Patients who have extrahepatic manifestations like glomerulonephritis or non-Hodgkin lymphoma can benefit from partial suppression of the hepatitis C virus through the treatment, which can stabilize their renal function or progression of malignancy, respectively.  

Pegylated interferon (PEG-IFN) and ribavirin treatment both are known to have side effects and can create compliance issues in patients.  Interferon therapy has many side effects, including fatigue, joint pain, flu-like symptoms, emotional irritability, hair loss, depression, bone marrow suppression, etc. Ribavirin can cause rash and hemolytic anemia. Due to bone marrow suppression caused by interferon and hemolytic anemia caused by Ribavirin, patients require routine lab work and close follow-up.  Patients with leukopenia and anemia may need administration of granulocyte colony-stimulating factor (G-CSF) and erythropoietin administration. Also, thrombocytopenia remains a common side effect with interferon therapy; this is especially important because patients who have hepatitis C virus-induced cirrhosis may have thrombocytopenia at baseline, which can become severe due to interferon therapy and can cause complications of bleeding. Patients who have hepatitis C virus-induced cirrhosis and thrombocytopenia with platelet counts lower than 70,000/µL are sometimes treated with eltrombopag which was approved by FDA in 2008 originally for treatment of thrombocytopenia and idiopathic thrombocytopenic purpura (ITP) however eltrombopag is known to cause venous thromboembolism and drug-induced liver injury and should be used cautiously and only if required.[49] Another less common side effect of interferon and ribavirin combination therapy is retinopathy, and patients should be encouraged to have an ophthalmologic evaluation before and after the treatment. Patients who have diabetes should also try to achieve strict control of the blood sugars as the presence of insulin resistance reduces the chances of achieving viral eradication. Patients with chronic hepatitis C infection who have renal insufficiency or on dialysis should receive antiviral treatment with a reduced dose of pegylated interferon (PEG-IFN) before patients are considered for renal transplant.  Ribavarin should be avoided in hemodialysis patients or patients with renal insufficiency due to an increased risk of hemolytic anemia. Patients with chronic hepatitis C infection who also have a co-existing HIV infection should also receive combination therapy and should be aggressively treated.  These patients are usually immunosuppressed at baseline due to their HIV infection and should be very closely monitored with frequent laboratory monitoring while being on combination therapy.[48]

In the last decade, antiviral treatment for hepatitis C virus infection has improved dramatically with development of newer therapeutic oral agents called direct-acting antiviral drugs (DAAs) including simeprevir, sofosbuvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, etc. showing very high cure rates regardless of negative factors like unfavorable HCV genotype, coexisting HIV infection or high viral load. These agents are taken for 8 to 12 weeks and are very effective with viral eradication, are well tolerated and have less side effects however the number of people receiving the treatment remains low due to the cost of treatment, insurance denials, lack of willingness of providers to treat the HCV-infected person with these medications and certain factors like homelessness and substance use that can impact medication compliance.[50]

Hepatitis D

Patients who are coinfected with the hepatitis D virus and hepatitis B virus usually receive treatment with pegylated interferon (PEG-IFN). Oral nucleoside or nucleotide analogs have limited or no efficacy and are not useful. Unfortunately, the treatment of hepatitis D has not changed in a long time, and pegylated interferon remains the only effective treatment. In one study, patients who had hepatitis D virus infection with coexisting HIV infection had therapy with tenofovir, which showed good efficacy. Still, the exact mechanism of this efficacy is not known, and more studies are required.[51]

Hepatitis E

Treatment for acute hepatitis E infection is supportive. Immunosuppressed patients and solid organ transplant recipients can develop chronic hepatitis E infection and can have treatment with ribavirin. Pegylated interferon (PEG-IFN) has been used successfully but was associated with many adverse effects like cholestasis.[52]  

Hepatitis G

There is currently no recommended treatment for hepatitis G.  Patients who develop liver cirrhosis have treatment with similar treatment modalities used to treat cirrhosis of any other etiology.[24]

Autoimmune Hepatitis

The mainstay of treatment has been the use of corticosteroids alone or in combination with azathioprine. The majority of patients respond to initial therapy and go into remission; however, once the treatment ceases, the majority of patients relapse as well. Treatment is necessary for patients who have tenfold or more greater than the upper limit of normal serum AST levels, fivefold or more greater than the upper limit of normal serum AST levels and twofold or more greater than the upper limit of normal serum gammaglobulin level or bridging necrosis on the histologic exam. Timely treatment initiation in these patients results in the slowing of disease progression. Patients who have inactive cirrhosis, intolerance to medications, and pre-existing comorbid conditions usually do not receive treatment. Patients who have end-stage decompensated liver disease are usually referred for liver transplantation and not started on medications. 

Once liver function tests normalize after initial therapy, prednisone dosing tapers off, and patients are put on maintenance therapy with azathioprine alone.  Azathioprine therapy usually terminates one year after liver function tests remain within the reference range. In the initial phases of treatment, liver enzymes need frequently checking. If enzymes do not return to the reference values in the first two months of therapy, steroid dose needs to increase. Those patients who do not tolerate prednisone well can try on budesonide as an alternative agent. Cyclosporine has been used in several studies as well and has shown good efficacy. Treatment usually stops if patients achieve remission, develop significant side effects from therapy, or have an incomplete or no response to therapy.

Patients who achieve remission report significant improvement in symptoms with aminotransferases. They return to the reference value range and a reduction in inflammatory activity on liver biopsy. These patients can be tapered off steroids over a few months and later on can stop azathioprine as well.  The typical duration of treatment is approximately two years before the withdrawal of treatment is considered. Histologic changes on the liver biopsy often lag behind clinical and laboratory improvement by 3 to 6 months, which the clinician should consider before stopping the treatment. A small number of patients deteriorate with worsening of their symptoms, laboratory markers, and histologic features while being on combination therapy. Fulminant hepatic failure can happen in these patients, and they have a high short-term mortality rate. These patients should be put on high-dose prednisone alone or in combination with azathioprine.  Patients who do not tolerate high-dose prednisone should have a trial of cyclosporine, tacrolimus, mycophenolate, or budesonide. If they do not respond to these medications also, then they should be considered for early liver transplantation. Some patients respond only partially to the treatment and have some improvement in the symptoms, lab values, and liver histology but cannot satisfy remission criteria. These patients require indefinite treatment with frequent dose adjustments as necessary to prevent relapse or further deterioration. These patients should also be monitored for early signs of hepatic decompensation and should obtain a referral for early liver transplantation.

Patients who experience significant side effects from therapy should also stop the treatment. Long-term use of corticosteroids can cause many adverse effects, including acne, hirsutism, cushingoid features, cardiac arrhythmias, diabetes mellitus, mood swings, osteoporosis, fractures, hypertension, cataracts. Azathioprine can cause cholestasis, nausea, vomiting, pancytopenia, pancreatitis, and rash; however, most of the patients tolerate azathioprine better than high-dose steroids. Each patient requires an individual assessment for side effects, and dose should be adjusted, or treatment should be withdrawn depending on the severity of the side effects and treatment tolerability. Patients should receive calcium and vitamin D supplementation to prevent the development of osteoporosis, and bone density scans are an annual requirement. If patients end up developing osteoporosis, then it should be treated with bisphosphonate therapy. Patients on azathioprine therapy should also have a routine complete blood count.

About half the patients experience relapse within six months after the treatment is withdrawn, and the majority of patients experience relapse within three years of treatment. Patients who experience relapse are usually put back on the original treatment regimen, and most of them experience remission; however, after stopping the treatment the second time, many patients experience relapse again. Patients who relapse twice will receive indefinite low-dose combination therapy.  Therapy should not stop or undergo abrupt withdrawal as it can result in a severe life-threatening exacerbation.

Patients who do not tolerate therapy do not respond to treatment or have decompensated cirrhosis need a referral for liver transplantation.  Recurrence of autoimmune hepatitis after liver transplantation is rare, and usually, the long-term outlook is excellent. Patients who have autoimmune hepatitis-primary biliary cirrhosis overlap syndrome will have treatment with ursodiol in combination with immunosuppressive therapy.[53]

Alcoholic Hepatitis

Patients with mild alcoholic hepatitis do not require treatment and should be counseled for alcohol cessation, maintain proper nutrition, and should take supplemental vitamins, including folic acid and thiamine. Patients who have significant coagulopathy should receive vitamin K. Patients who are at high risk of experiencing alcohol withdrawal should obtain appropriate treatment. Patients with severe alcoholic hepatitis have high mortality, on the other hand, compared to patients with mild alcoholic hepatitis. These patients can present with various complications like hepatic encephalopathy, gastrointestinal bleeding, and should be hospitalized for closer monitoring. Patients can benefit from steroids in the short-term, but in the long-run, only alcohol abstinence is effective. After maintaining alcohol abstinence for 6 to 12 months, alcoholic hepatitis continues to improve and usually resolve in a few years. Patients who have difficulty abstaining from alcohol should attend a rehabilitation program. Malnourishment is common in patients with alcoholic hepatitis, and patients should be encouraged to take about 60 to 100 grams of dietary protein per day, except when patients have hepatic encephalopathy. Patients with ascites with suspicion for spontaneous bacterial peritonitis should be treated with antibiotics empirically. Liver transplantation can be an option in end-stage liver disease, but patients must abstain from alcohol for at least six months before they are candidates for transplantation.[54]

Differential Diagnosis

Many other disorders can present with similar symptoms and signs commonly found in patients of hepatitis. Patients with acute and chronic active viral hepatitis infections usually present with malaise, fatigue, low-grade fever, anorexia, loss of weight, nausea, vomiting, etc. Patients can be completely normal on physical exam or may have right upper quadrant pain with hepatomegaly, urticarial rash and may show signs of dehydration. In advanced stages of liver disease from chronic viral hepatitis, patients may present with hematemesis, ascites, pedal edema, encephalopathy, etc. These symptoms and signs are observable with many other acute or chronic infectious or non-infectious conditions. 

Patients who have viral or bacterial gastroenteritis, acute cholecystitis, acute cholelithiasis, tuberculosis, HIV, liver abscess, malignancies such as pancreatic cancer, lymphoma, and hepatocellular cancer, small bowel obstruction, peptic ulcer disease can all have an overlap of these signs and symptoms. Patients with severe congestive heart failure can present with pedal edema, ascites, and hepatomegaly due to hepatic congestion. Patients who have gastrointestinal bleeding from other causes, including cirrhosis due to advanced non-alcoholic steatohepatitis, can present similarly like patients with advanced liver disease due to viral, autoimmune, or alcoholic hepatitis. 

Patients with hereditary hemochromatosis can present in their 50s or 60s with abdominal pain, fatigue, weakness, and symptoms and signs of liver failure. Hereditary hemochromatosis is an autosomal recessive disease that disrupts the body's iron regulation, and excess iron becomes deposited in various organs of the body, including the liver. Diagnosis is usually by checking serum iron, serum ferritin, and serum transferrin levels. A liver biopsy may become necessary to evaluate for the degree of fibrosis and to differentiate it from other disorders of the liver, including viral or autoimmune hepatitis. Patients can present with joint pain, and some patients complain of pain in the knuckles of the first two fingers called the "iron fist" sign. This sign is specific to hereditary hemochromatosis but is not present in all the patients.[55] Patients with drug-induced hepatitis and congenital hepatopathies can also have a similar presentation, and a careful history is integral while evaluating the patients. Drug-induced liver injuries have become more common, and more than a thousand drugs have been identified, and studies are underway to find out more about them. Patients with drug-induced liver injuries can be completely asymptomatic, with only lab abnormalities of elevated aminotransferases to acute or chronic hepatitis or acute liver failure and remain one of the biggest causes of emergency liver transplants. The unregulated use of herbal and dietary supplements has created a new challenge to identify and treat patients promptly.[56]

Patients with autoimmune hepatitis and alcoholic hepatitis can also have similar symptoms as in viral hepatitis, especially when the disease is advanced, and patients experience severe liver dysfunction. A careful history, laboratory studies, and liver biopsy, when necessary, should be obtained to differentiate them. Further information on how to diagnose and differentiate these conditions are obtainable from the evaluation section of this article. 

Since there are so many conditions that can present with similar symptoms and signs, it is not within the scope of this article to discuss every condition listed in the differential diagnosis.

• Liver abscess
• Hepatocellular cancer
• Pancreatic cancer
• Drug-induced hepatitis
• Autoimmune hepatitis
• Acute cholangitis
• Acute cholecystitis and biliary colic
• Blunt abdominal trauma
• Pancreatitis
• Gastroenteritis
• Cholelithiasis
• Intussusception
• Peptic ulcer disease
• Small-bowel obstruction

Prognosis

Viral Hepatitis

Prognosis of viral hepatitis depends on the virus, causing the infection. 

Hepatitis A infection is usually a mild self-limiting illness.  Patients infected with hepatitis A virus develop lifelong immunity against subsequent infection from hepatitis A.  Overall, mortality is very low, and complications including relapse, jaundice, and fulminant liver failure are rare. Patients who are immunocompromised, the elderly, and young children are at higher risk compared to healthy adults.[4]

Patients with hepatitis B infection are at risk of developing chronic hepatitis and cirrhosis as well as hepatocellular carcinoma as a consequence.  Fulminant hepatic failure happens in about 0.5 to 1% of the patients with hepatitis B infection.  But when there is fulminant hepatic failure, the mortality rate is about 80%. Chronic liver disease from chronic hepatitis B infection is responsible for approximately 650000 fatalities per year globally.[57]

Patients who get infected with the hepatitis C virus end up developing a chronic infection in 50% to 60% of cases. These patients are at high risk of developing chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Chronic hepatitis C infection remains one of the leading reasons for liver transplantation. The hepatitis C related mortality rate in the United States increased till 2013 but has been declining since 2014 but remains elevated in developing countries.[58]

Patients who have chronic hepatitis B virus infection and then get coinfected with hepatitis D virus tend to develop chronic hepatitis D infection and leads to the development of chronic hepatitis more commonly compared to patients who only chronic hepatitis B infection and a majority of those patients end up developing end-stage liver disease and cirrhosis.[59]

Hepatitis E infection is a mild self-limiting illness like hepatitis A infection. But pregnant patients can have a high mortality rate of 15% to 25%. The exact mechanism of how it causes a high mortality rate in pregnant patients is not clear.[60]

Most patients are asymptomatic in acute infection with normal aminotransferase levels. Fulminant hepatic failure and chronic infections are rare with hepatitis G infection. Although co-infection with HBV and HCV is common, it does not increase the severity of the disease.[9]

Autoimmune Hepatitis

The prognosis of autoimmune hepatitis is directly related to the severity of liver inflammation. Patients who have severe symptoms and signs of extensive liver damage on the initial presentation have a high mortality rate and bad prognosis compared to those patients in whom the initial disease is mild. Patients who frequently relapse or do not respond to treatment also have a worse prognosis. About half of the patients who have severe autoimmune hepatitis die within five years without treatment.  Patients who respond well to the treatment initially and stay in remission have a very good prognosis, and a 10-year life expectancy is about 90%. About 70% of the children diagnosed with autoimmune hepatitis end up requiring treatment during adulthood. About 10% of patients require liver transplantation. The development of hepatocellular carcinoma is less common in patients who have cirrhosis from autoimmune hepatitis compared to those patients who have cirrhosis from other causes.[10]

Alcoholic Hepatitis

The prognosis of patients who have alcoholic hepatitis depends on whether they abstain from alcohol and the degree of liver injury. Patients who abstain from alcohol strictly show improvement in liver function over months to years and liver biopsy also reveals the resolution of histologic changes. Patients who continue to drink alcohol continue to get worse with the development of cirrhosis. In these patients, a 5-year survival rate is only about 30%. Patients who have hepatic encephalopathy, coagulopathy, or jaundice, along with alcoholic hepatitis have a mortality rate of about 40%. Various prognostic scoring methods have been developed in the last two decades and include the discriminant function (DF) model for end-stage liver disease (MELD) score, Glasgow alcoholic hepatitis score (GAHS), and asymmetric dimethylarginine (ADMA) score. A discussion on these prognostic scoring methods is beyond the scope of this article.[54]

Complications

Viral Hepatitis

Complications of viral hepatitis include chronic infection with chronic active hepatitis, acute or subacute hepatic necrosis, cirrhosis, liver failure, hepatocellular carcinoma in patients with hepatitis B or C infection. Patients who have hepatitis B infection are at high risk of developing chronic infection. Patients are also at significant risk of developing hepatocellular carcinoma, which is responsible for 45% of primary liver cancer worldwide. About 1% of patients can also develop fulminant hepatic failure, and the mortality rate is about 80% in those patients. About 75 to 85% of patients who get infected with hepatitis C end up developing chronic infection and about 20% of those patients end up developing cirrhosis and eventually hepatocellular carcinoma. Cirrhosis developing from hepatitis C infection is a leading cause of liver transplantation in the United States. Cirrhosis itself can cause multiple complications, including hepatic encephalopathy, portal hypertension, ascites, spontaneous bacterial peritonitis, variceal bleed, hepatorenal syndrome, etc. Patients who have chronic hepatitis C infection also have a high risk of developing extrahepatic complications including cryoglobulinemia which can lead to rash, vasculitis, and glomerulonephritis secondary to deposition of immune complexes in the small vessels, non-Hodgkin lymphoma, focal lymphocytic sialadenitis, autoimmune thyroiditis, porphyria cutanea tarda, lichen planus, etc.[61]

Autoimmune Hepatitis

Complications of autoimmune hepatitis are similar to complications of viral hepatitis, or patients can develop end-stage liver disease with cirrhosis, which can lead to complications like ascites, hepatic encephalopathy, coagulopathy, variceal bleed, portal hypertension, and severe malnutrition. Hepatocellular carcinoma can occur but is not as common as seen in patients with chronic hepatitis B or C infection. Some patients can develop primary biliary cirrhosis and eventually developed hepatocellular carcinoma.[44]

Alcoholic Hepatitis

Complications of alcoholic hepatitis are similar to that of cirrhosis. Patients can develop variceal bleeding with portal hypertension, hepatic encephalopathy, coagulopathy, and severe thrombocytopenia, ascites, and spontaneous bacterial peritonitis.[54]

Treatment of Complications of Hepatitis

Patients developing cirrhosis and its complications many times require close monitoring with hospitalization and emergency treatment. Patients with variceal bleed require immediate resuscitation, protection of the airway, endoscopy with sclerotherapy or band ligation of the varices. Many patients require administration of somatostatin or octreotide. Patients with hepatic encephalopathy are usually put on rifaximin or lactulose as an outpatient and require close monitoring. Worsening of encephalopathy involves hospitalization. These patients are typically maintained on a low protein diet. Patients with severe coagulopathy require vitamin K administration and platelet transfusion if necessary. Patients with ascites are treated with diuretics, control of dietary salt intake, and may need frequent paracentesis with intermittent use of intravenous albumin. Some patients develop spontaneous bacterial peritonitis and require antibiotics.  The majority of patients require frequent hospitalizations due to complications of cirrhosis, and their quality of life is significantly altered.  Patients who develop hepatocellular carcinoma may require chemotherapy, radiation therapy, and liver transplantation.

Deterrence and Patient Education

Patient education is key to preventing and controlling hepatitis, especially viral and alcoholic hepatitis. Patients who have viral hepatitis must obtain education educated regarding the importance of routine follow-up and the importance of monitoring the disease progression and development of complications. They should learn about the importance of personal hygiene, including frequent handwashing. People who are traveling to endemic areas should be advised not to drink untreated water or ingest shellfish or raw seafood, and fruits and veritable should always be eaten after being cooked or after being peeled. Patients who have hepatitis A should not handle food for others until they stop shedding the virus. Patients should receive instruction about not sharing any articles, including toothbrushes, razors, or needles that have the potential for contamination with saliva, semen, or blood. All the patients should avoid using hepatotoxic agents, including alcohol and acetaminophen. Patients who are having a disease progression with liver disease should be referred to a gastroenterologist or hepatologist promptly. Patients with features of liver damage that includes liver fibrosis, cirrhosis, hepatocellular carcinoma, and features of portal hypertension should be monitored with routine labs. 

All pregnant women should have screening for hepatitis B infection and HIV infection. If they test positive for hepatitis B infection, then both the mother and newborn should be treated appropriately. Neonates who are born to mothers who have hepatitis B infection should be given hepatitis B vaccination within 12 hours of birth to prevent the transmission of the virus. Sometimes the mother needs to be treated actively during pregnancy, also depending on her viral load and HIV status.

Healthcare workers should maintain strict infection control practices, and those at risk of contracting hepatitis C virus infection should be offered appropriate health education, testing, and treatment as required. Healthcare providers should be able to identify the individuals at risk and test them for hepatitis C infection. These individuals include people who have a history of injection drug use, persons infected with HIV, individuals with blood-borne exposure to hepatitis C virus, and certain healthcare workers.

Patients with autoimmune hepatitis should be tested for other autoimmune diseases and should be referred early in their illness to a gastroenterologist or a hepatologist. Referral to other specialists like endocrinology or rheumatology is necessary if the clinician finds evidence for other autoimmune disorders during the workup. Patients should have counsel about the importance of side effects of treatment, including corticosteroids, as many of them would require long term treatment.

Patients who are at risk of developing alcoholic hepatitis or who already have alcoholic hepatitis should be educated about abstaining from alcohol completely and about serious health consequences of continued alcohol use. Patients should be referred to rehabilitation programs and should be encouraged to attend them regularly.[62]

Vaccination

Hepatitis A

Patients should understand the importance of preventing hepatitis, and it requires emphasis that preventing hepatitis is much easier than treating hepatitis. Viral hepatitis is preventable with vaccination.

Individuals traveling to areas where hepatitis A is endemic should be offered hepatitis A vaccine one month before traveling. Other patients who should be offered hepatitis A vaccine are individuals who use illicit drugs, men who have sex with men, patients with chronic liver disease, patients who are awaiting liver transplant or are recipients of a liver transplant, patients receiving clotting factor concentrates, and individuals who work with hepatitis virus-infected primates in laboratories. 

Patients can receive inactivated hepatitis A virus vaccine through the intramuscular route with a booster dose recommended after six months. Patients exposed to hepatitis A virus can also be given postexposure prophylaxis with hepatitis A immunoglobulin and should have it within 48 hours of exposure for higher effectiveness. Typically it is recommended for individuals who are in close contact with the patients of hepatitis A infection at home or in daycare centers.[63]

Hepatitis B

Hepatitis B vaccine is recommended for all the infants as a part of the routine immunization schedule. It should also be given to the adults at high risk of infection including patients on dialysis, healthcare workers who are at risk of exposure to blood and body fluids, people with sexual partners who have hepatitis B infection, sexually active persons who are not in a long-term monogamous relationship, persons who are being evaluated or treated for sexually transmitted infections, men who have sex with men, individuals who share needles or syringes, household contacts of individuals who have hepatitis B infection, residents and staff of facilities for developmentally disabled persons and in correctional facilities, victims of sexual assault or abuse, people with chronic liver disease, HIV infection or diabetes, individuals who have a known sexual or household contact with an acutely infected patient, and those individuals who had an inadvertent percutaneous or mucosal exposure. Neonates who are born to mothers who have hepatitis B infection should be given hepatitis B vaccination within 12 hours of birth to prevent the transmission of the virus. Plasma-derived or recombinant hepatitis B vaccines are used and are highly effective with more than 95% rate of seroconversion. Infants are given initial vaccination at the time of birth with repeat vaccination at 1 to 2 months and 6 to 18 months. For the adults, after the initial vaccination, it is repeated at one month and six months. Some clinicians recommend booster dose at 5 to 10 years. Individuals can also receive postexposure prophylaxis with hepatitis B immunoglobulin. It is usually given after liver transplantation to those patients who were infected with the hepatitis B virus to reduce the damage to the liver allograft. Patients requiring frequent transfusion of blood products or factor concentrates like patients of hemophilia should also receive the vaccination; however, with higher usage of recombinant factor and better techniques for the viral elimination process have decreased the risk of infection significantly.[64]

Hepatitis C   

Vaccine for hepatitis C is currently not available, and immunoglobulin is not proven to be effective in preventing transmission. It is, therefore, of high importance to put infection control practices in place and prevent the contamination of blood, organs, and semen and prevent the transmission of the virus into donor pools with better screening and improved viral elimination techniques.[64] Pregnant mothers testing positive for the hepatitis C virus should have their infants monitored and tested for hepatitis C virus infection and should be strictly followed and offered treatment.

Hepatitis D

Since the hepatitis D virus occurs as a coinfection when hepatitis B virus infection is present, transmission can be prevented by immunizing patients against hepatitis B virus. Currently, it is not possible to prevent hepatitis D virus superinfection in patients with chronic hepatitis B infection.

Hepatitis E

Vaccine for hepatitis E virus infection does not exist at this time, and the administration of immunoglobulin does not prevent the disease.[65]

Hepatitis G

Patients who are transplant recipients or get frequent transfusions, injection drug users, hemodialysis patients, and men who have sex with men are the groups that are at increased risk. However, there is currently not a vaccine available for hepatitis G.[24]

Enhancing Healthcare Team Outcomes

This article discusses hepatitis, which is a complex disease and requires an interprofessional approach from healthcare providers to tackle it. The article discusses strategies to prevent hepatitis through patient education and vaccination and the importance of closer monitoring for disease progression and complications. These strategies require significant interprofessional communication and care coordination by physicians, including primary care physicians and specialists, nurses, pharmacists, and other health professionals, to enhance patient-centered care.  Nursing needs to work closely with the patient to ensure they understand their disease, are compliant with medications and vaccines, and note progress or lack thereof. Pharmacists are crucial to ensuring the proper medications at the correct dose are in the therapy regimen, and that there are no interactions. Any issues noted by any member of the interprofessional healthcare team need to be shared and charted, so everyone operates from the same data. These measures can help improve the outcomes and aid to patient safety and can also help enhance team performance. [Level 5]