Liver Diseases

Chapter 11

INFLAMMATORY BOWEL AND LIVER DISEASES

Inflammatory Bowel Disease (IBD)

Introduction  

• Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. The term IBD is commonly used to two bowel disease having many similarities but the conditions usually have distinctive morphological appearance. These two conditions are ulcerative colitis and Crohn’s disease.

• Ulcerative colitis: This condition causes long-lasting inflammation and sores (ulcers) in the innermost lining of large intestine (colon) and rectum. Classically, ulcerative colitis begins in the rectum, and in continuity extends upwards into the sigmoid colon, descending colon, transverse colon, and sometimes may involve the entire colon. The colonic contents may rarely back flow in the terminal ileum in continuity, causing ‘back wash ileitis’ in about 10% of cases.

• Crohn's disease: Crohn’s disease may involve any portion of the gastrointestinal tract but affect most commonly 15-25 cm of the terminal ileum which may extend into the caecum and sometimes into the ascending colon. Both ulcerative colitis and Crohn's disease usually involve severe diarrhoea, abdominal pain, and fatigue and weight loss   

Causes 

• Immunological factors: The exact cause of IBD is unknown, but IBD is the result of a defective immune system. A properly functioning immune system attacks foreign organisms, such as viruses and bacteria, to protect the body. In IBD, the immune system responds incorrectly to environmental triggers, which causes inflammation of the gastrointestinal tract.

•  Genetic factors: There is about 3 to 20 time higher incidence of occurrence of IBD in first degree relatives. This is due to genetic defect causing diminished epithelia barrier function. • There is approximately 50% chance of development of IBD (Crohn’s disease about 60%, ulcerative colitis about 6%) in monozygotic twins. However there is no clear link between the abnormal genes and IBD.

• Exogenous factors: Microbial factors: Microbial factors (bacteria, viruses, protozoa and fungi) have been suspect but without definite evidence. Psychosocial factors: It has been observed that individuals who are unduly sensitive, dependent on others and unable to express themselves, or some major life events such as illness or death in the family, divorce, interpersonal conflicts etc. suffer from irritable colon or have exacerbation of symptoms. Smoking: Role of smoking in causation of Crohn’s disease has been reported. iv) Oral contraceptives: An increased risk to develop Crohn’s disease with long term use of oral contraceptive has been found in some studies but there is no such increased risk of ulcerative colitis.  

Pathophysiology of Inflammatory Bowel Disease 

• The location and appearance of inflammatory lesions differs between the two forms. In Crohn’s disease, inflammatory lesions extend through the bowel wall and develop simultaneously in separate areas. Granuloma formation occurs first, followed by ulceration and abscess formation, fistula may form between the affected areas and the bladder, vagina or rectum. With repeated episodes, the gut wall assumes a cobblestone appearance, with permanent scarring and constriction. The characteristic lesion of UC is the crypt abscess, pus filled, necrotic lesion that starts at the bases of any of the tubular glands of the intestinal mucous membrane. These lesions ulcerate and bleed during flares, then heal with scarring and constriction.

• In a normal individual, there is lack of immune responsiveness to dietary antigens and commersal flora in the intestinal lumen. The mechanism responsible for this is by activation of CD4+T cell secreting cytokines inhibitory to inflammation (IL-10, TGF-β) which suppress inflammation in the gut wall. In IBD, this immune mechanism of suppression of inflammation is defective and thus results in uncontrolled inflammation. In both types of IBD, activated CD4+T cells are present in the lamina propria and in the peripheral blood. These cells either activate other inflammatory cells macrophages and B cells. There are two main types of CD4+T cells in IBD.

• Crohn’s disease begins with crypt inflammation and abscesses, which progress to tiny focal aphthoid ulcers. These mucosal lesions may develop into deep longitudinal and transverse ulcers with intervening mucosal edema, creating a characteristic cobblestoned appearance to the bowel. Transmural spread of inflammation leads to lymphedema and thickening of the bowel wall and mesentery. Mesenteric fat typically extends onto the serosal surface of the bowel. 

• ublesome aspects of Crohn’s disease. Non-caseating granulomas can occur in lymph nodes, peritoneum, the liver, and all layers of the bowel wall. Although pathognomonic (a characteristic sign or symptom of a disease that can be used to diagnosis) when present, granulomas are not detected in about half of patients with Crohn’s disease. The presence of granulomas does not seem to be related to the clinical course.  

Sign and Symptoms 

• Inflammatory bowel disease symptoms vary, depending on the severity of inflammation and where it occurs. Symptoms may range from mild to severe. Signs and symptoms that are common to both Crohn's disease and ulcerative colitis include: Diarrhoea, fever and fatigue, abdominal pain and cramping, blood in stool, reduced appetite, unintended weight loss. Other symptoms may include: Constipation, sores or swelling in the eyes, draining of pus, mucus, or stools from, around the rectum or anus (fistula), joint pain and swelling, mouth ulcers, rectal bleeding and bloody stools, swollen gums, tender, red bumps (nodules) under the, skin which may turn into skin ulcers. 

 Diagnosis 

Crohn’s disease is diagnosed through a medical history, physical exam, imaging tests to look at the intestines, and lab tests.

• General investigation: Physical examination include, checking for signs such as paleness (caused by anemia) or tenderness in the abdomen, skin rash, swollen joints, or mouth ulcers and tenderness in stomach (caused by inflammation) and recording of patient’s history. 

• Computed tomography (CT) scan: Computerized tomography scans use a combination of X-rays and computer technology to create images. CT scans can diagnose both Crohn’s disease and the complications seen with the disease.

• Magnetic resonance imaging (MRI): MRI uses a magnetic field and pulses of radio wave energy to provide pictures of organs and structures inside the body. The pathologic entities of a fistula, a sinus tract, and an abscess can be detected in the static anorectal region by using MRI. 

• Barium enema: This diagnostic test allows evaluating entire large intestine with an X-ray. Barium, a contrast solution, is placed into bowel using an enema. Sometimes air is added as well. The barium coats the lining, creating a features of rectum, colon and a portion of small intestine. This test is rarely used anymore, and it can be dangerous because the pressure required to inflate and coat the colon can lead to rupture of the colon. For people with severe symptoms, flexible sigmoidoscopy combined with a CT scan is a better alternative.   

Treatment 

• Treatment for IBD depends on the seriousness of the disease. Most people are treated with medication. Some people whose symptoms are triggered by certain foods are able to control the symptoms by avoiding foods that upset their intestines, like highly seasoned foods or dairy products. Each person may experience ulcerative colitis differently, so treatment is adjusted for each individual. Emotional and psychological support is also important. The main aims of treatment are to: 

1. Reduce symptoms, known as inducing remission (a period without symptoms)
2. Maintain remission. 

Anti-inflammatory Drugs: 

 Anti-inflammatory drugs are often the first step in the treatment of inflammatory bowel disease. They include:

• Aminosalicylates (ASAs): Such as Sulfasalazine, Mesalamine, Balsalazide and Olsalazine are medications that help to reduce inflammation and effective in ulcerative colitis.

• Corticosteroids: These drugs, which include prednisone and hydrocortisone are a more powerful type of medications used to reduce inflammation. They can be used with or instead of ASAs to treat a flare-up if ASAs alone are not effective.

• Immunosuppressants: Immunosuppressants such as Azathioprine, 6-mercaptopurine, methot-rexate, cyclosporine are often used and can make a marked improvement at a low dose with few side effects. Other drugs may be given to relax the patient or to relieve pain, diarrhoea, or infection. Occasionally, symptoms are severe enough that the person must be hospitalized. 

Other Medications:  

Additional medications are required to manage specific symptoms of ulcerative colitis:

• Antibiotics: People with ulcerative colitis who run fevers will likely take antibiotics to help prevent or control infection. (e.g., Metronidazole, Ciprofloxacin, Rifaximin etc.)

• Antidiarrhoeal medications: For severe diarrhoea, loperamide may be effective. Use antidiarrhoeal medications with great caution, however, because they may increase the risk of toxic megacolon.

• Bowel rest: Sometimes Crohn’s disease symptoms are severe and a person may need to rest bowel for a few days to several weeks. Bowel rest involves drinking only clear liquids or having no oral intake. Nutritions are provided to the patient intravenosly through a special catheter, or tube, inserted into a vein in the patient’s arm.

• Surgery: Even with medication treatments, up to 20% of people will need surgery to treat their Crohn’s disease. Although surgery will not cure Crohn’s disease, it can treat complications and improve symptoms.

Jaundice 

• Jaundice is a condition in which a person’s skin and the whites of the eyes are discoloured yellow due to an abnormally increased level of bile pigments, bilirubin in the blood and body tissue resulting from liver diseases such as cirrhosis, hepatitis or gallstones. 

Causes of Jaundice 

• The liver breaks down old, inefficient red blood cells in a process (hemolysis) and releases large amounts of bilirubin. The excess amount of bilirubin results in toxic and can cause jaundice. The liver also manufactures the other components of bile. Normally, the liver metabolizes and excretes the bilirubin in the form of bile. However, if there is a disruption due to infection or damage in this normal metabolism and production of bilirubin, jaundice may result.

• The excess amount of bilirubin can be toxic and it is important to eliminate from the body as fast as it is produced. There are three basic ways this process can go wrong and can cause jaundice.

The liver itself can be temporarily or permanently damaged, reducing its ability to break down bilirubin (mix it with bile) and move it into the gallbladder.

The gallbladder or its bile ducts can become blocked, preventing excretion of bilirubin into the intestine. Bilirubin will then back up into the liver and then into the bloodstream.

Any condition that leads to very rapid destruction of red blood cells can create too much bilirubin for even a healthy liver to handle. Again, the excess is carried into the bloodstream.

 Some Causes of Jaundice due to Poor Liver Function include:

• Viral hepatitis: Hepatitis A, B, C, D and E can all cause temporary liver inflammation.Types B and C can also cause chronic, lifelong inflammation.

• Medication-induced hepatitis: This may be caused by alcohol, erythromycin, methotrexate, amiodarone, statins (e.g., lovastatin, pravastatin, rosuvastatin), nitrofurantoin, testosterone, oral contraceptives, acetaminophen and many other medications.

• Autoimmune hepatitis: In this condition, the body’s immune system attacks its own liver cells. Autoimmune hepatitis is more common in people and families with other autoimmune diseases, such as lupus, thyroid disease, diabetes, or ulcerative colitis. Primary biliary cirrhosis is another autoimmune condition of the liver and involves inflammation of the bile ducts.

• Gilbert’s syndrome: This harmless inherited condition is quite common, affecting about 2% of the population. Minor defects in the liver’s metabolism of bilirubin cause jaundice to appear in times of stress, exercise, hunger or infection.  

Some Causes of Jaundice due to Obstruction (Blockage) include:

• Gallstones: Formed in the gallbladder, gallstones can block the bile ducts, preventing bile (and bilirubin) from reaching the intestine. Sometimes, the bile ducts may become infected and inflamed.

• Cholestasis: A condition in which the flow of bile from the liver is interrupted. The bile containing conjugated bilirubin remains in the liver instead of being excreted.

• Newborn jaundice: Jaundice in newborn babies can be caused by several different conditions, although it is often a normal physiological consequence of the newborn’s immature liver. Even though it is usually harmless under these circumstances, newborns with excessively elevated levels of bilirubin from other medical conditions (pathologic jaundice) may suffer devastating brain damage (kernicterus) if the underlying problem is not addressed. Newborn jaundice is the most common condition requiring medical evaluation in newborns.

Types of Jaundice 

Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects. The three categories are:

• Pre-hepatic jaundice: If an infection or medical condition makes the red blood cells break down sooner than usual, bilirubin levels rise. This is known as pre-hepatic jaundice. Conditions which may trigger this include malaria, sickle cell anaemia, thalassaemia, Gilbert’s syndrome, hereditary spherocytosis and Crigler-Najjar syndrome.

• Intra-hepatic jaundice: If the liver is damaged, it may be less able to process bilirubin and reduces the liver’s ability to metabolize and excrete bilirubin leading to a buildup of unconjugated bilirubin in the blood which causes intra-hepatic jaundice. The liver damage may be a result of causes that include hepatitis, alcoholic liver disease, glandular fever, liver cancer, illegal drug use, and paracetamol overdose. Obesity and non-alcoholic fatty liver disease can be a cause of cirrhosis of the liver and jaundice.

Pathophysiology  

1. Conjugated hyperbilirubinemia results from reduced secretion of conjugated bilirubin into the bile, such condition occurs in patients with hepatitis, or it results from impaired flow of bile into the intestine, such condition occurs in patients with biliary obstruction. Bile formation is sensitive to various hepatic insults, including high levels of inflammatory cytokines, such as may occur in patients with septic shock.

1. High levels of conjugated bilirubin may secondarily elevate the level of unconjugated bilirubin. Although the mechanism of this effect is not fully defined, one likely cause is reduced hepatic clearance of unconjugated bilirubin that results from competition with conjugated bilirubin for uptake or excretion. 

Symptoms  

Common signs and symptoms seen in individuals with jaundice include:

• Yellow discolouration of the skin, mucous membranes, and the whites of the eyes 
• Light-colored stools
• Dark-colored urine
• Itching of the skin
• Nausea and vomiting
• Abdominal pain
•  Fever
• Weakness
•  Loss of appetite
• Confusion, 
• Swelling of the legs and abdomen. 

Newborn jaundice: In newborn’s, as the bilirubin level rises, jaundice will typically progress from the head to the trunk, and then to the hands and feet. Additional signs and symptoms that may be seen in the newborn include:

• Poor feeding
• Lethargy
• Changes in muscle tone
• High-pitched crying and seizures

Diagnosis 

• Physical Examination: The physical examination should focus primarily on signs of liver disease other than jaundice, including bruising, spider angiomas, gynecomastia, testicular atrophy, and palmar erythema. An abdominal examination to assess liver size and tenderness is important. The presence or absence of ascites also should be noted.

• Urine Test: Urine can be tested for urobilinogen, which is produced when bilirubin is broken down. Finding high or low levels can help pinpoint the type of jaundice.

• Serum Testing: First-line serum testing in a patient presenting with jaundice should include a complete blood count (CBC) and determination of bilirubin (total and direct fractions), aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase, and alkaline phosphatase levels. 

Imaging Studies: 

• Ultrasound: It is very useful for detecting gallstones and dilated bile ducts. It can also detect abnormalities of the liver and the pancreas.

•  Computerized tomography (CT) scan: A CT scan is an imaging study which provides more details of all the abdominal organs, useful in distinguishing an obstructing lesion from hepatocellular disease in the evaluation of a jaundiced patient.

• Magnetic resonance imaging (MRI): MRI is an imaging study that uses a magnetic field to examine the organs of the abdomen. It can be useful for detailed imaging of the bile ducts.

• Endoscopic retrograde cholangiopancreatography (ERCP): ERCP is a procedure that involves the introduction of an endoscope (a tube with a camera at the end) through the mouth and into the small intestine. A dye is then injected into the bile ducts while X-rays are taken. It can be useful for identifying stones, tumors or narrowing of the bile ducts.

•  Liver Biopsy: Liver biopsy can be particularly helpful in diagnosing autoimmune hepatitis or biliary tract disorders. Patients with primary biliary cirrhosis are almost always positive for antimitochondrial antibody, and the majority of those affected by primary sclerosing cholangitis have antineutrophil cytoplasmic antibodies.

• Laparoscopy (peritoneoscopy): It allows direct inspection of the liver and gallbladder, without the trauma of a full laparotomy. Unexplained cholestatic jaundice warrants laparoscopy occasionally and diagnostic laparotomy rarely.

Treatment 

Treatment of jaundice typically requires a diagnosis of the specific cause in order to select suitable treatment options. Treatment would target the specific cause, rather than the jaundice itself.

• Pre-hepatic jaundice: In treating prehepatic jaundice, the objective is to prevent the rapid breakdown of red blood cells that is causing bilirubin levels to build up in the blood. In cases of infections, such as malaria, the use of medication to treat the underlying infection is usually recommended. For genetic blood disorders, such as sickle cell anaemia or thalassaemia, blood transfusions may be required to replace the red blood cells.

• Intra-hepatic jaundice: In cases of intra-hepatic jaundice, the objective is to repair any liver damage, although the liver can often repair itself over time. The treatment is therefore to prevent any further liver damage occurring.

• Post-hepatic jaundice: In most cases of post-hepatic jaundice, surgery is recommended to unblock the bile duct system. During surgery, it may also be necessary to remove:   

The gallbladder 

Asection of the bile duct system

T section of the pancreas to prevent further blockages occurring

•  In certain cases of newborn jaundice, exposing the baby to special coloured lights (phototherapy) or exchange blood transfusions may be required to decrease elevated bilirubin levels.

Complication

• omplications of jaundice include sepsis especially cholangitis, biliary cirrhosis, pancreatitis, coagulopathy, renal and liver failure.

•  The itching associated with jaundice and cholestasis can sometimes be so severe that it causes patients to scratch their skin “raw”, have trouble sleeping, and, rarely, even to commit suicide.

• Most complications that arise are a result of the underlying cause of jaundice, not from jaundice itself. For example, jaundice caused by a bile duct obstruction may lead to uncontrolled bleeding due to a deficiency of vitamins needed for normal blood clotting.

Hepatitis 

Hepatitis means injury to the liver with inflammation of the liver cells. Toxins, certain drugs, some diseases, heavy alcohol use, bacterial and viral infections can all cause hepatitis. Hepatitis is also the name of a family of viral infections that affect the liver; the most common types in the India and Asian countries are hepatitis A, hepatitis B and hepatitis C.

Types of Viral Hepatitis: A group of viruses known as the hepatitis viruses cause most cases of liver damage worldwide. Common viruses cause hepatitis include A, B, C, D, E and G (95% cause of viral hepatitis). Other viruses include, Herpes simplex virus, Cytomegalovirus, Epstein-Barr virus, Yellow fever virus and Adenoviruses also cause hepatitis. 

Etiology

Most common cause of all viral hepatitis includes:

• Use of infected needle and syringes 
• Intravenous drug users
• Transfusion of infected blood and blood products
• Unprotected sexual contact with an infected 

Hepatitis A virus: Infection causes due to eating raw shellfish from water polluted with sewage and contaminated food and water. Travel or work in regions with high rates of hepatitis A.

Carrier of Hepatitis B virus: Some people with Hepatitis B never fully recover from the infection (chronic infection), they still carry the virus and can infect others for the rest of their lives. HBV can be transmitted between family members within households by contact of non-intact skin or mucous membrane with secretions or saliva containing HBV.

 Causes of Hepatitis C virus: Occurs as the result of percutaneous transmission of the hepatitis C virus through infectious blood. It can be passed from an infected mother to her baby. HCV can also be transmitted through household contact (sharing of personal items such as razors, toothbrushes, scissors and manicuring equipment within the same household).

Causes of Hepatitis D virus: HDV is transmitted parenterally, it can replicate independently within the hepatocyte, but it requires HBs Ag for propagation. Sexual transmission is less efficient than with HBV. Perinatal transmission is rare.

Causes of Hepatitis E virus: Infection spread by fecally contaminated water within endemic areas. On the other hand, in non-endemic areas, the major mode of the spread of HEV is food borne, especially undercooked pork.

Causes of Hepatitis G virus: It has been identified in all ethnicities, and 1% - 4% of worldwide blood donors are carriers of the virus at the time of blood donation.

Pathophysiology of Hepatitis  

Hepatitis A Hepatitis A is a highly contagious liver infection caused by the hepatitis A virus. The epatitis viruses that cause inflammation that affects liver’s ability to perform normal function. Nearly everyone who develops Hepatitis A makes a full recovery; it does not lead to chronic disease. Mild cases of hepatitis A do not require treatment, and most people who are infected recover completely with no permanent liver damage.

It is small sized (27 nm), non-enveloped, single stranded RNA virus. Related to enteroviruses, (Enteroviruses are a genus of positive sense single-stranded RNA viruses) formerly known as enterovirus 72, now put in its own family heptovirus. It is very difficult to grow in cell culture:

 

Pathophysiology After oral inoculation the virus is transported across the intestinal epithelium. After travelling through the mesenteric veins to the liver, the virus enters hepatocytes, where replication of hepatitis A virus (HAV) occurs exclusively within the cytoplasm via RNA-dependent polymerase. The liver damage is due to direct killing of hepatocytes and by the host’s immune system response to infected hepatocytes indicates inflammation of liver. Microscopically there is spotty parenchymal cell degeneration, with necrosis of hepatocytes, with disruption of liver cell cords. 

Hepatitis B Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV), which infects the liver and causes an inflammation called hepatitis, originally known as “serum hepatitis”. It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead to liver cancer or cirrhosis (a condition that causes permanent scarring of the liver). Most people infected with hepatitis B as adults recover fully, even if their signs and symptoms are severe. Infants and children are much more likely to develop a chronic hepatitis B infection. Although no cure exists for hepatitis B, a vaccine can prevent the disease. 

Hepatitis B Virus: Hepatitis B virus is a hepadna virus – 'hepa' from hepatotrophic (attracted to the liver) and 'dna' because it is a DNA virus and it has a circular genome composed of partially double-stranded DNA. The viruses replicate through an RNA intermediate form by reverse transcription and in this respect they are similar to retroviruses. Although replication takes place in the liver, the virus spreads to the blood where virus-specific proteins and their corresponding antibodies are found in infected people. Blood test for these proteins and antibodies are used to diagnose the infection. It has long incubation period i.e. 30 to 180 days. Virus does not kill hepatocytes but the infected cells die itself as a result of immune system attack after recognition of viral antigen on cell surface.

Pathophysiology: HBV infection in itself does not lead to the death of infected hepatocytes. The host’s immune response to viral antigens is thought to be the cause of the liver injury in HBV infection. Liver damage arises from cytolytic effects of the immune system's cytotoxic T lymphocytes (CTL) which attempt to clear infection by killing infected cells. The cellular immune response, rather than the humoral immune response, seems to be primarily involved in disease pathogenesis. Induction of antigen-specific T-lymphocyte response is thought to occur when host T lymphocytes are presented with viral epitopes by antigen-presenting cells in lymphoid organs. These antigen-specific T cells mature, expand and then migrate to the liver. In acute HBV infection, most HBV DNA is cleared from hepatocytes through non-cytocidal effects of inflammatory byproducts of CD8+ T lymphocytes, stimulated by CD4+ T lymphocytes, notably interferon-gamma and tumour necrosis factor-alfa. These cause down-regulation of viral replication, and trigger direct lysis of infected hepatocytes by HBV-specific CD8+ cytotoxic T cells. In contrast, people with chronic HBV infection display weak, infrequent, and narrowly focused HBVspecific T-cell responses, and the majority of mononuclear cells in livers of chronic HBVinfected people are non-antigen-specific. 

Hepatitis C Hepatitis C is a liver disease caused by the hepatitis C virus (HCV). The virus can cause both acute and chronic hepatitis infection, ranging in severity from a mild illness lasting a few weeks to a serious, lifelong illness. Hepatitis C is usually spread through direct contact with the blood of infected person. The liver can swell and become damaged. In hepatitis C, unlike hepatitis B, liver cancer risk is only increased in people with cirrhosis and only 20% of hepatitis C patients get cirrhosis. The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (cirrhosis) and liver cancer.

 Hepatitis D: Hepatitis D is a serious liver disease caused by the hepatitis D virus (HDV) and relies on HBV to replicate. Hepatitis D virus (HDV) is an RNA virus and causes a unique infection that requires the assistance of viral particles from hepatitis B virus (HBV) to replicate and infect other hepatocytes. Its clinical course is varied and ranges from acute, self-limited infection to acute, fulminant liver failure. Chronic liver infection can lead to end-stage liver disease and associated complications. Simultaneous infection with HBV and HDV is known as coinfection and results in fulminant liver failure in 1% of patients. Complete clinical recovery and clearance of HBV and HDV coinfection, is the most common outcome. Chronic infection with HBV and HDV occurs in less than 5% of patients. Infection with HDV in a patient who is already positive for the hepatitis B surface antigen (HBsAg) is known as superinfection and results in fulminant liver failure in 5% of patients. Approximately 80- 90% develops chronic HDV infection. These patients progress more rapidly to develop cirrhosis and may develop hepatocellular carcinoma.

Etiology and Pathophysiology: The hepatitis E virus (HEV) genome contains 3 open reading frames (ORFs). The largest, ORF-1, codes for the non-structural proteins responsible for viral replication. ORF-2 contains genes encoding the capsid. The function of ORF-3 is unknown, but the antibodies directed against ORF-3 epitopes have been identified. HEV is an RNA virus of the genus Hepevirus. The virus is icosahedral and nonenveloped. It has a diameter of approximately 34 nanometres, and it contains a single strand of RNA approximately 7.5 kilobases in length. Four HEV genotypes have been identified. Genotypes 1 and 2 are considered human viruses; genotypes 3 and 4 are zoonotic and have been isolated from humans and animals. 

Symptoms 

Common symptoms of all viral hepatitis includes —

• Nausea and vomiting 
• Loss of appetite 
• Weakness and fatigue 
• Fever • Dark urine 
• Pale stool
• Jaundice 
• Stomach pain and side pain. 
• Abdominal pain 

1. Symptoms of Hepatitis A: In rare cases, hepatitis A can cause acute liver failure, which is a loss of liver function that occurs suddenly. People with the highest risk of this complication include those with chronic liver diseases and older adults.
2. Symptoms of Hepatitis B: Most infants and children with hepatitis B never develop signs and symptoms. Chronic infection with hepatitis B virus either may be asymptomatic or may be associated with a chronic inflammation of the liver failure (chronic hepatitis), leading to cirrhosis over a period of several years, kidney problems and sometimes chronically infected with HBV is also susceptible to infection with another strain of viral hepatitis . Person cannot become infected with hepatitis D unless he is already infected with HBV. Having both hepatitis B and hepatitis D makes it more likely may develop complications of hepatitis.
3. Symptoms of Hepatitis C: Generalized signs and symptoms associated with chronic hepatitis C include fatigue, marked weight loss, flu-like symptoms, muscle pain, joint pain, intermittent low-grade fevers, itching, sleep disturbances, nausea, diarrhoea, dyspepsia, cognitive changes, depression, headaches and mood swings.
4. Symptoms of Hepatitis D: The symptoms of hepatitis B and hepatitis D are similar, so it can be difficult to determine which disease is causing symptoms. In some cases, hepatitis D can make the symptoms of hepatitis B worse. It can also cause symptoms in people who have hepatitis B but who never had symptoms.
5. Symptoms of Hepatitis E: Other feature includes, malaise, arthritis, pancreatitis, aplastic anemia, thrombocytopenia etc. Some neurologic symptoms includes polyradiculopathy, Guillain–Barré syndrome, Bell palsy, peripheral neuropathy, ataxia and mental confusion.

Diagnosis 

• Blood test: Blood test used to detect antibodies made by the body in response to the virus that causes viral hepatitis. 

• Liver function tests: When hepatocytes become damaged by Hepatic virus, regular blood tests are helpful to measure the levels of liver enzymes. These enzymes can become elevated and releases into the blood. Liver function test includes: Alanine aminotransferase (ALT or “SGPT, Aspartate aminotransferase (AST or “SGOT”), Alkaline phosphatase and γ glutamyl transpeptidase (GGT or GGTP).

• Hepatitis A antibody, IgM: These antibodies typically develop 2 to 3 weeks after first being infected and persist for about 2 to 6 months. Hepatitis A IgM antibodies develop early in the course of infection, so a positive hepatitis A IgM test is usually considered diagnostic for acute hepatitis A in a person with signs and symptoms.

• TreatHepatitis B core antibody IgM: This is an antibody produced against the hepatitis B core antigen. It is the first antibody produced in response to a hepatitis B infection and, when detected, may indicate an acute infection. It may also be present in people with chronic hepatitis B when flares of disease activity occur.ment. 

• HBV surface antibody: The test for this antibody may sometimes be included in a panel to help determine if an infection has resolved or if a person has developed the antibody after receiving the hepatitis B vaccine and achieved immunity for protection against HBV.

• HDV Antibody Testing: IgM anti-HDAg antibody develops with acute HDV infection, becoming positive 7-15 days after onset of clinical illness and decline with recovery and resolution of HDV infection. During acute infection, HDV RNA can also be detected by polymerase chain reaction. After clearance of HDV, IgG anti-HDAg becomes positive.

 Prevention 

• Management should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. Travelers to endemic areas should avoid drinking water or other beverages that may be contaminated and should avoid eating uncooked shellfish.

Alcoholic Liver Disease

• Alcoholic Liver Disease is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of alcohol. The pathogenesis is not completely understood. Though alcoholic liver disease is most likely to occur in people who drink heavily over many years, the relationship between drinking and alcoholic liver disease is complex. Not all heavy drinkers develop alcoholic liver disease, and the disease can occur in people who drink only moderately.

• Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic liver disease often do not cause any symptoms.

•  Alcoholic liver disease usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic liver disease resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis. Of all chronic heavy drinkers, only 15–20% develops hepatitis or cirrhosis, which can occur concomitantly or in succession

Epidemiology

• Alcohol abuse is the most common cause of serious liver disease in Western societies. The true prevalence of alcoholic liver disease, especially of its milder forms, is unknown, because patients may be asymptomatic and never seek medical attention. 

Causes 

• Alcoholic liver disease occurs when the liver is damaged by the excessive consumption of alcohol. How alcohol damages the liver and why it does so only in a minority of heavy drinkers is not clear. It is known that the process of breaking down ethanol; the alcohol in beer, wine and liquor produces highly toxic chemicals, such as acetaldehyde. These chemicals trigger inflammation that destroys liver cells. Over time, web-like scars and small knots of tissue replace healthy liver tissue, interfering with the liver’s ability to function. This irreversible scarring, called cirrhosis, is the final stage of alcoholic liver disease. 

• Heavy alcohol use can lead to liver disease, and the risk increases with the length of time and amount of alcohol drink. But because many people who drink heavily or binge drink never develop alcoholic liver disease or cirrhosis, it is likely that factors other than alcohol play a role. These include.

• Other types of hepatitis: Long-term alcohol abuse worsens the liver damage caused by other types of hepatitis, especially hepatitis C. 

• Malnutrition: Many people who drink heavily are malnourished, either because they eat poorly or because alcohol and its toxic by-products prevent the body from properly absorbing and breaking down nutrients, especially protein, certain vitamins and fats. In both cases, the lack of nutrients contributes to liver cell damage. 

• Sex: Women have a higher risk of developing alcoholic liver disease than men do. This disparity may result from differences in the way alcohol is processed by women. 

• Genetic factors: A number of genetic mutations have been identified that affect the way alcohol is broken down in the body. Having one or more of these mutations may increase the risk of alcoholic liver disease.

Pathophysiology 

Some signs and pathological changes in liver histology include:

• Alcoholic liver disease is characterized by the inflammation of hepatocytes. Between 10% and 35% of heavy drinkers develop alcoholic liver disease. While development of hepatitis is not directly related to the dose of alcohol, some people seem more prone to this reaction than others. This is called alcoholic steato necrosis and the inflammation appears to predispose to liver fibrosis. Inflammatory.

• The Kupffer cells of the liver then phagocytose endotoxin, stimulating the release of TNF-alpha. TNFalpha then triggers apoptotic pathways through the activation of caspases, resulting in cell. death

• . Cirrhosis: A progressive and permanent type of fibrotic degeneration of liver tissue. Cirrhosis is a late stage of serious liver disease marked by inflammation (swelling), fibrosis (cellular hardening) and damaged membranes preventing detoxification of chemicals in the body, ending in scarring and necrosis (cell death). Between 10% to 20% of heavy drinkers will develop cirrhosis of the liver. Acetaldehyde may be responsible for alcohol-induced fibrosis by stimulating collagen deposition by hepatic stellate cells. 

Symptoms 

It may not have symptoms in the early stages. Symptoms tend to be worse after a period of heavy drinking. Digestive symptoms include:

1. Pain and swelling in the abdomen and tenderness
2. Decreased appetite and weight loss
3. Nausea and vomiting
4. Fatigue
5. Dry mouth and increased thirst
6. Bleeding from enlarged veins in the walls of the lower part of the esophagus

 Skin problems such as:

1. Yellow colour in the skin, mucus membranes, or eyes (jaundice)
2. Small, red spider-like veins on the skin
3. Very dark or pale skin
4. Redness on the feet or hands
5. Itching

Just about everyone who has alcoholic liver disease is malnourished. Drinking large amounts of alcohol suppresses the appetite, and heavy drinkers get most of their calories in the form of alcohol.

Complications 

Complications of alcoholic liver disease include:

• Increased blood pressure in the portal vein: Blood from the intestine, spleen and pancreas enters the liver through the portal vein. If scar tissue slows normal circulation through the liver, this blood backs up, leading to increased pressure within the vein (portal hypertension).

• Enlarged veins (varices): When circulation through the portal vein is blocked, blood may back up into other blood vessels in the stomach and esophagus. Massive bleeding in the upper stomach or esophagus from these blood vessels is a life-threatening emergency that requires immediate medical care. 

• Jaundice: It occurs when liver is not able to remove bilirubin; the residue of old red blood cells from blood. Bilirubin builds up and is deposited in skin and the whites of eyes, causing a yellow colour.

• Hepatic encephalopathy: A liver damaged by alcoholic liver disease has trouble removing toxins from body normally one of the liver’s key tasks. The buildup of toxins can damage brain, leading to changes in mental state, behaviour and personality (hepatic encephalopathy). Signs and symptoms of hepatic encephalopathy include forgetfulness, confusion and mood changes, and in the most severe cases, coma.

Diagnosis 

• Common considerations in alcoholic patients with jaundice include chronic pancreatitis with biliary strictures and pancreaticobiliary neoplasms. Changes in the mental status of patients with alcoholic liver disease do not always imply the presence of hepatic encephalopathy. Entities (e.g. subdural hematomas) should be excluded by obtaining a computed tomography (CT) scan of the brain.

• CBC Count: A complete blood cell (CBC) count commonly reveals some degree of neutrophilic leukocytosis with bandemia. Usually, this is moderate; however, rarely, it is severe enough to provide a leukemoid picture. Alcohol is a direct marrow suppressant, and moderate anemia may be observed. In addition, alcohol use characteristically produces a moderate increase in mean corpuscular volume. Thrombocytosis may be observed as part of the inflammatory response; conversely, myelosuppression or portal hypertension with splenic sequestration may produce thrombocytopenia. 

• Screening Blood Tests: Screening blood tests to exclude other conditions (appropriate in any patient with alcoholic liver disease) may include the following: Hepatitis B surface antigen (HBsAg) detects hepatitis B. Anti–hepatitis C virus by enzyme-linked immunosorbent assay (ELISA) detects hepatitis C. Ferritin and transferrin saturation detect hemochromatosis. Jaundice with fever can be caused by gallstones producing cholangitis and is suggested by a disproportionate elevation of the alkaline phosphatase (ALP) level. 

• Ultrasonography: Ultrasonography is the preferred imaging study in evaluating patients with suspected alcoholic liver disease. This modality provides a good evaluation of the liver and other viscera, and it permits guided liver biopsy.

• Liver Biopsy: Liver biopsy is not always required in the evaluation of alcoholic liver disease, but it may be useful in establishing the diagnosis, in determining the presence or absence of cirrhosis, and in excluding other causes of liver disease.

Treatment

• In most patients with alcoholic liver disease, the illness is mild. Their short-term prognosis is good, and no specific treatment is required. Hospitalization is not always necessary. Alcohol use must be stopped, and care should be taken to ensure good nutrition; providing supplemental vitamins and minerals, including folate and thiamine, is reasonable. Patients who are coagulopathic should receive vitamin K parenterally. Anticipate symptoms of alcohol withdrawal, and manage them appropriately.

•  Liver Transplantation: Orthotopic liver transplantation is widely used in patients with end-stage liver disease. Most patients with active alcoholic liver disease are excluded from transplantation because of ongoing alcohol abuse. In most liver transplantation programs, patients must abstain from alcohol for at least 6 months before they can be considered for transplantation, and a thorough psychosocial evaluation must demonstrate that patients have a low likelihood of reverting to alcohol abuse.

• Surgical Considerations: Patients with acute alcoholic liver disease are at high risk of developing hepatic failure following general anesthesia and major surgery. Because postoperative mortality rates are high, surgery should be avoided in the setting of acute alcoholic liver disease unless it is absolutely necessary. If patients remain abstinent, alcoholic liver disease usually resolves over time, permitting surgery to be undertaken with a substantially reduced risk.