Hepatitis

• 1. Introduction

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  Hepatitis, an inflammation of the liver tissue, was already killing people when Hippocrates wrote about it around 400 B.C. He described a group of patients who all died within two weeks. Near the end, he wrote, the patient "soon raves, becomes angry, talks nonsense and barks like a dog." The name itself comes from Greek: hêpar means liver, and -itis means inflammation. Today hepatitis is tied to more than a million deaths every year. Most of those deaths come indirectly, through liver scarring or liver cancer. Yet some people with hepatitis feel nothing at all, while others turn yellow, lose their appetite and cannot get out of bed. Why does one disease behave so differently from person to person? What can set off the inflammation, when the list runs from five separate viruses to a wild mushroom? And how did a scientist collecting blood samples around the world end up opening the way to a vaccine?

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• 2. Phases of Illness

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  About one to two weeks after the first vague symptoms, the skin and the whites of the eyes turn yellow. That yellowing is the middle stage of acute viral hepatitis, which moves through three phases. The first is the prodromal phase, the stretch before specific symptoms appear. It feels like flu, with fatigue, nausea, vomiting, poor appetite, joint pain and headaches. Fever shows up mostly with hepatitis A and E. Late in this phase, urine darkens and stools turn clay-colored.

  The yellow stage can last up to four weeks. By then the flu-like complaints usually fade, but the liver swells and the upper right abdomen aches. In 10 to 20 percent of people, the spleen enlarges too.

  Recovery runs on different clocks for different viruses. Hepatitis A and E clear completely within one to two months. Most hepatitis B cases take three to four months. Few hepatitis C cases clear on their own. Liver blood tests can stay abnormal for a while after the symptoms are gone.

  Six months is the dividing line between acute and chronic. In roughly 2 to 20 percent of people infected with hepatitis B and D together, liver cells die in massive numbers. Doctors call this fulminant hepatitis. Among pregnant women with hepatitis E, the figure is 15 to 20 percent. Patients bruise and bleed easily, then grow confused, disoriented and sleepy. Death can come from brain swelling, gut bleeding, sepsis, respiratory failure or kidney failure. Mortality in fulminant cases rises above 80 percent, yet survivors often recover completely, and a liver transplant can save a life.

  Chronic hepatitis is quieter. It often announces nothing and turns up only when a screening blood test is run. Jaundice arrives late and usually signals advanced disease. Because the liver helps regulate hormones, chronic inflammation can cause acne, abnormal hair growth and missed periods in women.

  The viruses behind hepatitis B and C do not directly trigger most of the cell death. Infected liver cells alert the immune system, and the resulting inflammation does the damage. Natural killer cells lead the first response, and in chronic B and C their function is impaired.

  Years of this cycle of injury and repair leave scar tissue. Extensive scarring is called cirrhosis, and it permanently limits what the liver can do. It brings fluid in the abdomen, swollen legs and weight loss. It can also lead to confusion from hepatic encephalopathy, swollen veins in the esophagus called esophageal varices, kidney failure called hepatorenal syndrome, and liver cancer.

  Age at infection shapes the odds. Hepatitis B turns chronic in about 90 percent of infants who catch it at birth, compared with about 1 percent of young adults. When hepatitis D arrives after hepatitis B, chronic infection follows in 80 to 90 percent of cases.

  Hepatitis C is the stubborn one. It becomes chronic in 85 to 90 percent of people, and cirrhosis shows up in about 16 percent twenty years after infection. Among people with stable cirrhosis from hepatitis C, survival is 96 percent at three years, 91 percent at five and 79 percent at ten. Once the cirrhosis becomes decompensated, meaning it is worsening, five-year survival falls to 50 percent.

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• 3. Five Viruses

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  Hepatitis A and hepatitis E travel by the fecal-oral route, meaning contaminated food and water. They are more common in developing countries, and neither one turns into chronic hepatitis. That makes them the mild pair of the five viruses that cause hepatitis.

  Hepatitis B, C and D spread when blood or mucous membranes meet infected blood and body fluids. Viral particles have been found in saliva and breast milk. Even so, kissing, sharing utensils and breastfeeding do not spread the virus unless those fluids reach open sores or cuts.

  Hepatitis D is a defective virus. It cannot replicate without hepatitis B, so it is only ever found in people who also carry B. This is why stopping hepatitis B also stops hepatitis D.

  Hepatitis C has an unusual modern history. In the 1970s and 1980s, blood transfusions were a major route of spread. After widespread screening of blood products began in 1992, the risk of catching hepatitis C from a transfusion fell from about 10 percent in the 1970s to about 1 in 2 million today.

  The global tally from 2015 is enormous. Hepatitis A struck about 114 million people that year. Chronic hepatitis B affected about 343 million and chronic hepatitis C about 142 million.

  Hepatitis E is mostly a disease of young adults. It accounts for more than 55,000 deaths a year, with about 20 million people thought to be infected. Pregnancy makes it far more dangerous, with death rates as high as 30 percent in the third trimester. Animals may act as a reservoir that feeds human infection.

  The World Health Organization has classified hepatitis D as carcinogenic to humans, as it has for B and C. Its risk groups differ by region. In the United States and Northern Europe they are injection drug users and people who have had multiple transfusions, while in the Mediterranean the virus is common among people already carrying hepatitis B.

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• 4. Other Culprits

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  Eighty grams of alcohol a day in men, or forty in women, sustained over years, is the threshold linked to alcoholic hepatitis. For scale, the source equates one beer or four ounces of wine with 12 grams. The disease develops in 10 to 20 percent of heavy drinkers. It sits on a ladder of worsening liver disease that runs from fatty liver to alcoholic hepatitis, then cirrhosis, then liver cancer, and the first rungs are the most reversible.

  Women face higher risk of alcoholic hepatitis and its complications than men, probably because of higher body fat and differences in how they metabolize alcohol. Binge drinking, poor nutrition and obesity add to the danger. As much as 20 percent of people with alcoholic hepatitis also carry hepatitis C, and that combination speeds the march to cirrhosis and cancer.

  Medicines are a second route. Paracetamol damages the liver in a predictable, dose-dependent way. Isoniazid, a tuberculosis antibiotic, causes unpredictable reactions that vary from person to person. Amoxicillin-clavulanate is the most common cause of drug-induced liver injury, and paracetamol toxicity is the leading cause of acute liver failure in the United States and Europe.

  Herbal remedies and dietary supplements are easy to overlook. They are the most common cause of drug-induced hepatitis in Korea. A United States network that tracks drug-induced liver injury tied more than 16 percent of cases to them. The National Institutes of Health maintains a database called LiverTox so consumers can look up compounds associated with liver injury. Industrial and natural toxins also belong on the list, including carbon tetrachloride and the wild mushroom Amanita phalloides.

  Another route needs no alcohol at all. Non-alcoholic steatohepatitis, or NASH, is fatty liver with added inflammation and cell death. It is strongly associated with obesity, insulin resistance, diabetes and metabolic syndrome. In the United States it affects about 11 million people, and 9 to 25 percent of patients develop cirrhosis. Imaging can show fat in the liver, but only a biopsy can show the inflammation and fibrosis that define NASH.

  In autoimmune hepatitis, the immune system attacks liver cells. It usually affects young women, though any age and either sex can be hit. About one in four to one in three patients have no symptoms at all. Many also have other autoimmune diseases, and the risk of liver cancer rises by about 1 percent for each year of illness.

  Inherited disorders can inflame the liver too. In Wilson's disease, copper builds up in the liver and brain, causing cirrhosis and dementia, and it tends to appear in childhood. Hemochromatosis loads the body with iron and usually shows up after age 50. Alpha-1-antitrypsin deficiency makes liver cells accumulate an abnormal protein.

  Parasites reach the liver as well. The dog tapeworm forms cysts there, and two liver flukes live in the bile ducts and cause progressive scarring. Then there is ischemic hepatitis, nicknamed shock liver, where reduced blood flow from heart failure, shock or sepsis sends enzyme levels into the thousands. It usually resolves once the underlying problem is treated.

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• 5. Reading the Liver

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  Two liver enzymes, AST and ALT, rise in most cases of hepatitis, whether or not the person feels ill. The pattern between them tells a story. In alcoholic steatohepatitis, AST exceeds ALT by more than two to one. In NASH, ALT leads by more than one and a half to one.

  A liver biopsy cannot tell the two apart, because both look identical under the microscope. Yet biopsy is still the gold standard when blood tests fall short. It reveals the exact extent and pattern of inflammation and fibrosis, and no scan can match that. Ultrasound, CT and MRI can spot fat and the lumpy surface of cirrhosis, but none can detect inflammation itself. Because biopsy is invasive and carries a small but real risk of bleeding, it is rarely the first test.

  For viral hepatitis, the answer is usually in the blood. Within the first week of infection, IgM antibodies appear. Later, and after recovery, IgG antibodies take over and can persist for years. A patient positive for IgG but negative for IgM is considered immune, through either past infection or vaccination.

  Screening aims to find infections before symptoms start. For hepatitis B, a blood test looks for the surface antigen. A follow-up test on the same sample separates acute from chronic infection. The list of people advised to be screened is long. It includes pregnant women, blood and organ donors, people on hemodialysis and those born in countries where at least 2 percent of the population carries the virus.

  For hepatitis C, screening looks for antibodies, and a second test for viral RNA confirms chronic disease. In the United States, adults born between 1945 and 1965 should be screened once. So should anyone who received blood products or organs before 1992, or a tattoo in an unregulated setting.

  Hepatitis A needs no chronic screening, since it never becomes chronic. The goal is checking immunity in people at high risk, such as travelers to endemic areas, so that those without protection can be vaccinated.

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• 6. Prevention and Treatment

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  A newborn about to leave the hospital in the United States receives the first dose of the hepatitis B vaccine before discharge. Two more doses follow before 18 months. If the mother carries hepatitis B surface antigen, the baby also gets hepatitis immune globulin, and both must come within 12 hours of birth.

  The hepatitis A vaccine is recommended for all children beginning at age one, in two doses given 6 to 18 months apart. The results have been dramatic. In the United States, universal immunization cut hospital admissions and medical expenses for hepatitis A by two-thirds. New cases of hepatitis B fell 75 percent between 1990 and 2004, with the biggest drop among children and adolescents, likely reflecting guidelines adopted in 1999.

  No vaccine for hepatitis C or E is available in the United States. A group in China published an article on a hepatitis E vaccine in 2015, and by March 2016 the United States government was recruiting participants for a phase IV trial. Hepatitis C infections declined from the 1980s but began rising again in 2006, and the data cannot say whether needle exchange programs deserve credit for the earlier decline.

  Where vaccines are missing, habits fill the gap. Clean water, good hygiene and proper sewage handling block hepatitis A and E. Screened blood, safe needle practices and safe sex block B and C. For alcohol, the maximum recommendation is no more than four drinks on any day and fourteen a week for men, and three a day and seven a week for women.

  Treatment of hepatitis depends on the cause. For hepatitis A and E it is supportive, meaning rest, fluids and nutrition. Healthy adults with acute hepatitis B recover fully in 95 to 99 percent of cases and need no antivirals. Chronic hepatitis B calls for drugs that control viral replication, and the source lists seven approved in the United States. Entecavir and tenofovir are first-line choices, along with pegylated interferon, a weekly injection that is estimated to cost about $18,000 a year, against $2,500 to $8,700 for the oral drugs.

  The biggest change came with hepatitis C. Direct-acting antiviral drugs, which first appeared in 2011, attack proteins the virus needs to replicate. For genotype 1, the most common worldwide, a combination of sofosbuvir and ledipasvir for 12 weeks cures most patients, including many with advanced fibrosis or cirrhosis. A cure is defined as an undetectable viral load 12 weeks after treatment ends. The catch is money. That 12-week course has been estimated at US$94,500, and cost keeps these drugs from reaching low-resource nations.

  Some forms resist treatment. Hepatitis D has no effective therapy, and interferon alpha suppresses it only temporarily. NASH has no approved medication in the United States, and doctors recommend gradual weight loss and more exercise. Autoimmune hepatitis responds to corticosteroids, sometimes with azathioprine, and 66 to 91 percent of patients reach normal liver tests within two years, averaging 22 months.

  Severe alcoholic hepatitis is the hardest. Without treatment, 20 to 50 percent of patients may die within a month. Corticosteroids reduce short-term deaths, but nothing yet lowers the risk of dying between three and twelve months. First-line care is treating the alcoholism itself, since people who stop drinking completely can reverse liver damage and live longer.

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• 7. Jaundice Through History

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  Clay tablets from around 3000 B.C. hold the earliest known observations of jaundice. The ancient Sumerians believed the liver was the home of the soul. They blamed yellowing of the skin on a devil named Ahhazu attacking that organ.

  War gave hepatitis a long record of casualties. Poor sanitation made infectious jaundice a major killer of troops in the Napoleonic Wars, the American Revolutionary War and both World Wars. In World War II, an estimated 10 million or more soldiers were affected.

  A clue to the cause came from vaccination. Soldiers were given yellow fever vaccines stabilized with human serum, probably contaminated with hepatitis viruses, and epidemics of hepatitis followed. Researchers noted 89 cases of jaundice in the months after 3,100 vaccinations. When the seed virus strain was changed, no jaundice appeared in the next 8,000 vaccinations, which suggested a separate infectious agent.

  In the 1950s and 1960s, New York University researcher Saul Krugman carried this work into the Willowbrook State School in New York, a crowded facility for mentally disabled children where hepatitis was endemic. He first injected students with gamma globulin and saw temporary protection. Then he injected live hepatitis virus. He also mixed feces from infected students into milkshakes and fed them to newly admitted children.

  In 1966, Henry Beecher attacked the work in the New England Journal of Medicine. He argued that parents did not understand the risks they were consenting to, and that the research benefited others at the children's expense. Poor families, he said, often felt pressured to join the project to win admission to the school and its resources. Others defended Krugman for the knowledge gained, and Willowbrook is still a standard example in debates over medical ethics.

  The next breakthrough was an accident. Dr. Baruch Blumberg, a researcher at the NIH, was studying lipoprotein genetics rather than hepatitis. He traveled the world collecting blood samples to understand how disease, environment and genetics interact. In the blood of a hemophilia patient who had received many transfusions, he noticed an unexpected reaction with a protein from an indigenous Australian person. He called it the "Australia antigen."

  He found it more often in patients from developing countries, and in people with other diseases such as leukemia and Down Syndrome. Eventually he concluded it was linked to viral hepatitis. In 1970, David Dane isolated the hepatitis B virion at Middlesex Hospital in London, and the 42-nanometer particle became known as the Dane particle. The Australia antigen was renamed hepatitis B surface antigen, or HBsAg. Blumberg then built the first hepatitis B vaccine from plasma rich in that antigen, and he received the Nobel Prize in Medicine in 1976.

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• 8. Cost of Illness

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  A single hospital stay for hepatitis A in the United States cost an average of $6,900 in a 1997 report, adding up to around $500 million in total annual healthcare costs. Per case, direct costs are estimated at $1,817 and indirect costs at $2,459. The average infected adult loses 27 work days. Cost studies suggest vaccinating all adults is not feasible, but a combined hepatitis A and B vaccine for children and at-risk groups may be.

  Hepatitis B weighs more heavily where it is endemic. In 1997 it accounted for 3.2 percent of South Korea's total health care spending, with $696 million in direct costs, mostly for treating symptoms and complications. In the United States, hospitalization costs for chronic hepatitis B were $357 million in 1990 and $1.5 billion in 2003. They then held steady through 2006, possibly thanks to effective drugs and vaccination campaigns.

  Hepatitis C patients use the health care system often. In the United States, a person with hepatitis C costs about $691 a month. That rises to $1,227 for stable cirrhosis and $3,682 for worsening cirrhosis, almost five times the base figure. Studies speculate that the total cost reaches $6.5 billion a year in the United States. In Canada, 56 percent of costs tied to hepatitis C come from cirrhosis, which is the stage that careful screening and the newer cures aim to prevent.

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