Autoimmune hepatitis

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Autoimmune hepatitis
Autoimmune hepatitis - cropped - very high mag.jpg
Micrograph showing a lymphoplasmacytic interface hepatitis—the characteristic histomorphologic finding of autoimmune hepatitis. Liver biopsy. H&E stain.
Specialty Gastroenterology, hepatology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Often asymptomatic, fatigue, right upper abdominal pain, anorexia, nausea, jaundice, joint pain, rash
Complications Chronic liver disease, cirrhosis
Usual onsetBimodal presentation: 10-20 years of age, 40-50 years of age
DurationLifelong
TypesType 1, type 2, seronegative
CausesGenetic predisposition with environmental trigger
Risk factors Female gender, additional autoimmune disease
Diagnostic method Liver enzyme levels, antibody panels. Definitive: Liver biopsy
Differential diagnosis Primary biliary cholangitis
Primary sclerosing cholangitis
Treatment Prednisone, Azathioprine
Prognosis <50% survival if untreated, >90% survival if treated
FrequencyIncidence 1-2 per 100,000 per year
Prevalence 10-25 per 100,000

Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the liver to be inflamed. Common initial symptoms may include fatigue, nausea, muscle aches, or weight loss or signs of acute liver inflammation including fever, jaundice, and right upper quadrant abdominal pain. Individuals with autoimmune hepatitis often have no initial symptoms and the disease may be detected by abnormal liver function tests and increased protein levels during routine bloodwork or the observation of an abnormal-looking liver during abdominal surgery. [1]

Contents

Anomalous presentation of MHC class II receptors on the surface of liver cells, [2] possibly due to genetic predisposition or acute liver infection, causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis. This abnormal immune response results in inflammation of the liver, which can lead to further symptoms and complications such as fatigue and cirrhosis. [3] The disease is most often diagnosed in patients in their late teens or early 20s and between the ages of 40 and 50. It affects women more commonly than men. [4]

Signs and symptoms

Autoimmune hepatitis may present completely asymptomatic (12–35% of the cases), with signs of chronic liver disease, or acute or even fulminant hepatic failure. [5] [6]

People usually present with one or more nonspecific, long-lasting symptoms such as fatigue, general ill health, lethargy, weight loss, mild right upper quadrant abdominal pain, malaise, anorexia, itching, nausea, jaundice or joint pain especially affecting the small joints. Rarely, rash or unexplained fever may appear. In women, the absence of menstruation (amenorrhoea) is a frequent feature. Physical examination may be normal, but it may also reveal signs and symptoms of chronic liver disease. Many people have only laboratory abnormalities as their initial presentation, as unexplained increase in transaminases and are diagnosed during an evaluation for other reasons. Others have already developed cirrhosis at diagnosis. [6] Of note, alkaline phosphatase and bilirubin are usually normal.

Autoimmune hepatitis may overlap with other autoimmune conditions, mainly type 1 diabetes mellitus, ulcerative colitis, lupus, celiac disease, vasculitis, and autoimmune thyroiditis. [5]

Cause

The prevailing theory for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger (virus, drugs, herbs, immunizations), and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. [7] [8] [9]

There is no specific evidence of the cause. Sixty percent of patients have findings associated with chronic hepatitis but without serologic evidence of a viral infection. The disease is strongly associated with anti-smooth muscle autoantibodies. [10]

The exact genes and triggers responsible remain undefined, but studies show association of early-onset, severe disease with the HLA-DR3 serotype and late-onset disease with the HLA-DR4 serotype. [11]

Diagnosis

The diagnosis of autoimmune hepatitis is best achieved with a combination of clinical, laboratory, and histological findings after excluding other etiological factors (e.g. viral, hereditary, metabolic, cholestatic, and drug-induced liver diseases). The requirement for histological examination necessitates a liver biopsy, typically performed with a needle by the percutaneous route, to provide liver tissue.

Autoantibodies

A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased immunoglobulin G level. The presence of anti-mitochondrial antibody is more suggestive of primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value. [12]

Histology

Autoimmune hepatitis can be characterized histologically by the following nonspecific findings: [13] [14] [15] [16]

Diagnostic scoring

The Internal Autoimmune Hepatitis Group developed a standardized scoring system for clinical diagnosis in population studies but lacks value in individualized cases. [17] A simplified scoring system for clinical use incorporates titers of autoantibodies, total IgG levels, liver histology, and the exclusion of viral hepatitis for diagnostic scoring. [18]

Classification

On the basis of detected autoantibodies, autoimmune hepatitis can be classified into three subtypes but have no distinct clinical presentations.

Differential diagnosis

Other diagnoses to consider include conditions that may cause acute hepatitis or chronic liver inflammation that may be accompanied by cirrhosis:

Treatment

The choice for medical treatment should be based on the individual's severity of symptoms, quantitative elevation of liver enzymes and antibody levels, findings on liver biopsy, and ability to tolerate side effects of medical therapy.

Generally, treatment is not required in asymptomatic patients with normal liver enzyme and antibody levels and liver biopsies that do not demonstrate inflammation because these patients are at a low risk of disease progression. In symptomatic individuals with evidence of interface hepatitis and necrosis on liver biopsy, it is recommended to offer treatment especially if the patient is young and can tolerate the side effects of medical therapy. [25] [26]

The mainstay of treatment involves the use of immunosuppressive glucocorticoids such as prednisone during acute episodes and resolution of symptoms can be achieved in up to 60–80% of cases, although many will eventually experience a relapse. [27] In individuals with moderate to severe disease who may not tolerate glucocorticoids, lower dose prednisone monotherapy or combination with azathioprine is a reasonable alternative. Budesonide has been shown to be more effective in inducing remission than prednisone, but evidence is scarce and more data is needed before it can be routinely recommended. [28] Those with autoimmune hepatitis who do not respond to glucocorticoids and azathioprine may be given other immunosuppressives like mycophenolate, ciclosporin, tacrolimus, or methotrexate. [27] [29] [30] [31]

Liver cirrhosis can develop in about 7% to 40% of treated patients. People with the highest risk for progression to cirrhosis are those with incomplete response to treatment, treatment failure, and multiple relapses. Once cirrhosis develops, management of liver cirrhosis in autoimmune hepatitis is standard regardless of etiology. Liver transplantation is the standard of care in people presenting with fulminant liver failure or those with the progression of disease despite multiple lines of therapy. [32] [33] [34]

Prognosis

Without treatment, the ten-year survival rate for individuals with symptomatic autoimmune hepatitis is 50%. However, with treatment, the ten-year survival rate is above 90%. Despite the benefits of treatment, people with autoimmune hepatitis generally have a lower transplant-free survival than the general population. [35] [36] [37] Outcomes with liver transplant are generally favorable with a five-year survival greater than 80 percent. [4]

Presentation and response to therapy may differ according to race. African Americans appear to present with a more aggressive disease that is associated with worse outcomes. [38] [39]

There has been strong evidence that patients with autoimmune hepatitis can develop mental health disorders like schizophrenia and bipolar disorder later in their life. [40]

Epidemiology

Autoimmune hepatitis can develop in people of any race or age but occurs most frequently in women. [41] [42] [43] Eighty percent of cases are the type 1 subtype with women being affected 4 times more often than men; for the type 2 subtype, women are affected 10 times more often than men. [44] [45]

European studies suggest a disease incidence of 1 to 2 people affected per 100,000 population with a prevalence of 10 to 25 people per 100,000 population. [42] [46] [47] [48]

The disease has a bimodal peak occurring between the ages of 10 and 20 and then later in life between the ages of 40 and 50. [43] [48]

History

Autoimmune hepatitis was previously called "lupoid" hepatitis due to people having an associated autoimmune disease like system lupus erythematosus at time of diagnosis, which was believed to be its cause. It was originally described in the early 1950s. [49]

Related Research Articles

<span class="mw-page-title-main">Hepatitis</span> Inflammation of the liver

Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

<span class="mw-page-title-main">Alcoholic liver disease</span> Medical condition

Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis.

<span class="mw-page-title-main">Alcoholic hepatitis</span> Medical condition

Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. Patients typically have a history of at least 10 years of heavy alcohol intake, typically 8–10 drinks per day. It is usually found in association with fatty liver, an early stage of alcoholic liver disease, and may contribute to the progression of fibrosis, leading to cirrhosis. Symptoms may present acutely after a large amount of alcoholic intake in a short time period, or after years of excess alcohol intake. Signs and symptoms of alcoholic hepatitis include jaundice, ascites, fatigue and hepatic encephalopathy. Mild cases are self-limiting, but severe cases have a high risk of death. Severity in alcoholic hepatitis is determined several clinical prediction models such as the Maddrey's Discriminant Function and the MELD score.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

<span class="mw-page-title-main">Portal hypertension</span> Abnormally increased portal venous pressure

Portal hypertension is defined as increased portal venous pressure, with a hepatic venous pressure gradient greater than 5 mmHg. Normal portal pressure is 1–4 mmHg; clinically insignificant portal hypertension is present at portal pressures 5–9 mmHg; clinically significant portal hypertension is present at portal pressures greater than 10 mmHg. The portal vein and its branches supply most of the blood and nutrients from the intestine to the liver.

<span class="mw-page-title-main">Primary sclerosing cholangitis</span> Medical condition

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as yellow discoloration of the skin and eyes, itching, and abdominal pain.

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

<span class="mw-page-title-main">Hepatorenal syndrome</span> Human disease

Hepatorenal syndrome is a life-threatening medical condition that consists of rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure. HRS is usually fatal unless a liver transplant is performed, although various treatments, such as dialysis, can prevent advancement of the condition.

<span class="mw-page-title-main">Liver biopsy</span> Medical test involving removal of tissue sample from the liver

Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

<span class="mw-page-title-main">Anti-mitochondrial antibody</span> Autoantibodies against liver mitochondria, indicating primary biliary cholangitis

Anti-mitochondrial antibodies (AMA) are autoantibodies, consisting of immunoglobulins formed against mitochondria, primarily the mitochondria in cells of the liver.

Autoimmune Pancreatitis (AIP) is an increasingly recognized type of chronic pancreatitis that can be difficult to distinguish from pancreatic carcinoma but which responds to treatment with corticosteroids, particularly prednisone. Although autoimmune pancreatitis is quite rare, it constitutes an important clinical problem for both patients and their clinicians: the disease commonly presents itself as a tumorous mass which is diagnostically indistinguishable from pancreatic cancer, a disease that is much more common in addition to being very dangerous. Hence, some patients undergo pancreatic surgery, which is associated to substantial mortality and morbidity, out of the fear by patients and clinicians to undertreat a malignancy. However, surgery is not a good treatment for this condition as AIP responds well to immunosuppressive treatment. There are two categories of AIP: Type 1 and Type 2, each with distinct clinical profiles.

<span class="mw-page-title-main">Sheila Sherlock</span> British physician, hepatologist and educator (1918–2001)

Dame Sheila Patricia Violet Sherlock DBE, FRCP FRCPE FRS HFRSE FMGA FCRGA was a British physician and medical educator who is considered the major 20th-century contributor to the field of hepatology.

An overlap syndrome is a medical condition which shares features of at least two more widely recognised disorders. Examples of overlap syndromes can be found in many medical specialties such as overlapping connective tissue disorders in rheumatology, and overlapping genetic disorders in cardiology.

<span class="mw-page-title-main">Cirrhosis</span> Chronic disease of the liver, characterized by fibrosis

Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage to the liver leads to repair of liver tissue and subsequent formation of scar tissue. Over time, scar tissue can replace normal functioning tissue, leading to the impaired liver function of cirrhosis. The disease typically develops slowly over months or years. Early symptoms may include tiredness, weakness, loss of appetite, unexplained weight loss, nausea and vomiting, and discomfort in the right upper quadrant of the abdomen. As the disease worsens, symptoms may include itchiness, swelling in the lower legs, fluid build-up in the abdomen, jaundice, bruising easily, and the development of spider-like blood vessels in the skin. The fluid build-up in the abdomen may develop into spontaneous infections. More serious complications include hepatic encephalopathy, bleeding from dilated veins in the esophagus, stomach, or intestines, and liver cancer. Stages of cirrhosis include compensated cirrhosis and decompensated cirrhosis.

Secondary sclerosing cholangitis (SSC) is a chronic cholestatic liver disease. SSC is a sclerosing cholangitis with a known cause. Alternatively, if no cause can be identified, then primary sclerosing cholangitis is diagnosed. SSC is an aggressive and rare disease with complex and multiple causes. It is characterized by inflammation, fibrosis, destruction of the biliary tree and biliary cirrhosis. It can be treated with minor interventions such as continued antibiotic use and monitoring, or in more serious cases, laparoscopic surgery intervention, and possibly a liver transplant.

Thomas D. Schiano is an American specialist in liver transplantation, intestinal transplantation and in the diagnosis and treatment of acute and chronic liver disease. He serves as associate editor for the journals Hepatology and Liver Transplantation and has published more than 200 peer-reviewed articles and abstracts and more than 20 book chapters.

Hyperbilirubinemia is a clinical condition describing an elevation of blood bilirubin level due to the inability to properly metabolise or excrete bilirubin, a product of erythrocytes breakdown. In severe cases, it is manifested as jaundice, the yellowing of tissues like skin and the sclera when excess bilirubin deposits in them. The US records 52,500 jaundice patients annually. By definition, bilirubin concentration of greater than 3 mg/ml is considered hyperbilirubinemia, following which jaundice progressively develops and becomes apparent when plasma levels reach 20 mg/ml. Rather than a disease itself, hyperbilirubinemia is indicative of multifactorial underlying disorders that trace back to deviations from regular bilirubin metabolism. Diagnosis of hyperbilirubinemia depends on physical examination, urinalysis, serum tests, medical history and imaging to identify the cause. Genetic diseases, alcohol, pregnancy and hepatitis viruses affect the likelihood of hyperbilirubinemia. Causes of hyperbilirubinemia mainly arise from the liver. These include haemolytic anaemias, enzymatic disorders, liver damage and gallstones. Hyperbilirubinemia itself is often benign. Only in extreme cases does kernicterus, a type of brain injury, occur. Therapy for adult hyperbilirubinemia targets the underlying diseases but patients with jaundice often have poor outcomes.

Deirdre Kelly is an Irish clinician, academic, and author. She is Professor of Paediatric Hepatology at the University of Birmingham and Clinical Lead for National Paediatric Hepatitis C Operational Delivery Network. She chairs the Board of Pension Trustees at the General Medical Council and is a non-executive director at NHS Blood and Transplant.

References

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