Diseases of the Liver

Hepatitis

Key points

• Hepatitis, or liver inflammation, can be classified according to etiology, i.e., infectious or non-infectious, or duration, i.e., acute or chronic.
• Infectious hepatitides are often caused by hepatitis viruses A through E and rarely by bacterial, fungal, or parasitic agents.
• Excessive alcohol consumption, drugs or toxins, auto-immune disease, or lifestyle factors may cause non-infectious hepatitis.
• Laboratory findings usually include elevated transaminases ALT and AST.

Hepatitis is a state of inflammation of the liver, regardless of the cause. Liver inflammation is classified according to etiology, i.e., infectious or non-infectious, or duration, i.e., acute or chronic. Viral infections are the most common cause of infectious hepatitis, but bacteria or parasites can also cause infectious hepatitis. The most common causes of non-infectious hepatitis are alcohol abuse, drugs or toxins, and auto-immune diseases. Depending on the duration of the inflammation, hepatitis may be classified as acute, with a sudden onset, or chronic, lasting more than 6 months. The symptoms of hepatitis may vary from asymptomatic to mild, severe or life-threatening. 

Figure 1. Overview of different types of hepatitis, split into infectious and non-infectious etiology. Note that other than the 5 main hepatitis viruses, viruses such as Epstein-Barr (EBV), yellow fever, and cytomegalovirus (CMV), can cause hepatitis as well.

Viral Hepatitis

Key points

• Viral hepatitis can be acute or chronic.
• Serological testing is available for hepatitis viruses A, B, C, and sometimes D.
• Treatment is primarily supportive, but in chronic cases, interferon and protease inhibitors are occasionally used.
• Viral hepatitis can be fatal if left untreated due to liver failure or hepatocellular carcinoma; this is mostly the case in hepatitis viruses B or C.

General 

Viral hepatitis is hepatitis caused by a viral infection. Five main hepatitis viruses are responsible for the majority of viral hepatitis: hepatitis viruses A (HAV), B (HBV), C (HCV), D (HDV) and E (HEV). Viral hepatitis can be acute, with a sudden onset lasting only a few weeks, or chronic, lasting more than 6 months. 

Epidemiology

Worldwide, about 2.3 billion people are infected with one or more hepatitis viruses. Viral hepatitis results in around 1.4 million deaths yearly. Approximately 90% of all deaths were caused by liver failure or hepatocellular carcinoma due to chronic HBV and HCV infections. Viral hepatitis is most common in developing countries, but the incidence of viral hepatitis in Western countries is increasing.

Symptoms 

Regardless of which virus causes hepatitis, symptoms are quite similar in all cases. Acute viral hepatitis usually presents with malaise, loss of appetite, pain in the upper right quadrant of the abdomen, vomiting, nausea, diarrhea, joint pain and fever. Chronic viral hepatitis can be asymptomatic for a long time after an initial acute infection. The initial (acute) viral infection is often not recognised as hepatitis, but is often mistaken for the flu. After the acute symptoms have subsided, the virus remains latent causing asymptomatic damage to the liver. Eventually, when the liver is largely damaged, it cannot break down hemoglobin effectively, and jaundice can occur. Malaise, fatigue and weight loss are also symptoms that often occur in chronic hepatitis.

Risk factors 

Poor sanitation and lack of safe water are the major risk factors for HAV and HEV infections. In addition, traveling to areas of high endemicity without being immunized is a risk factor for HAV. Contact with objects that might be contaminated with blood (like used needles or syringes) is a risk factor for HBV, HCV and HDV, just like sex with a person infected with a hepatitis virus.

Cause 

Other than the 5 main hepatitis viruses, viruses such as Epstein-Barr (EBV), yellow fever, and cytomegalovirus (CMV), can cause hepatitis. In HAV and HEV, ingestion is the transmission route, while HBV, HCV, and HDV are transmitted by parenteral contact.

The different hepatitis viruses are discussed in more detail in the Infectious Diseases chapter.

Diagnosis

In non-viral hepatitis, the diagnosis usually relies on the patient’s history, physical examination and blood tests that check the functioning of the liver. As in almost all types of hepatitis, laboratory examination shows a typical elevation of the transaminases AST and ALT. Bilirubin, AP and gamma-GT levels may vary between normal to (slightly) elevated. Liver function can be decreased, resulting in lower albumin and prolonged prothrombin time. 

A hepatitis virus serological test panel can detect antibodies for HAV, HBV, HCV and sometimes HDV. Additionally, other immunological and genomic tests are available. In acute viral hepatitis, it is not helpful to perform radiological examinations. However, in chronic viral hepatitis, an ultrasound can be performed to search for complications of a chronic infection, such as liver cirrhosis, splenomegaly or signs of hepatocellular carcinoma. 

Treatment

Specific treatments other than supportive therapy, rest, and fluids are often unavailable for an acute hepatitis virus infection. Medication, including interferon, protease inhibitors, and antivirals, can be used in chronic infections. Combinations of these medications are common. In case of severe liver damage, a liver transplant may be necessary. Vaccines are available to prevent an infection with HAV and HBV. The HAV vaccine is also protective against HEV; the HBV vaccine against HDV. There is no vaccine against HCV.

Prognosis 

An acute HAV infection is usually self-limiting without permanent damage. However, chronic (untreated) viral hepatitis, especially HBV and HCV, may eventually lead to liver cirrhosis or hepatocellular carcinoma, which can be fatal.

Non-Viral Hepatitis

Key points

• Non-viral hepatitis can be caused by bacteria, fungi or parasites.
• Men are twice more likely to be affected with non-viral hepatitis than women.
• Microorganisms that cause non-viral hepatitis mostly enter the liver through the portal vein and are therefore generally located in the right lobe.
• Non-viral liver infections often present with abdominal pain in the right upper quadrant radiating to the shoulder and a painful liver on palpation. 

General

In contrast to viral infections, bacterial, fungal and parasitic infections usually do not cause diffuse hepatitis but lead to abscesses or granulomatous hepatitis. The right hepatic lobe is the predilection site for non-viral infections since the right lobe is larger than the left lobe and receives blood from the portal vein, through which most microorganisms enter the liver.

Epidemiology

Liver infections with a microorganism other than viruses are rare. Parasitic infections are more common in Africa, Asia and South America than in Australia, Europe and North America. In Europe, the prevalence of liver abscesses is 0,25%. The worldwide incidence is 2,3 per 100.000 people.

Symptoms 

Non-viral liver infections practically always cause fever, with or without chills. Patients can experience pain in the right upper quadrant of the abdomen, radiating to the right shoulder. Icterus is not a common sign except in extremely large liver abscesses. The liver may be painful on palpation. Up to 10% of the patients may be in septic shock on presentation.

Risk factors 

Living in a (sub)tropic area or frequently traveling to these areas increases the risk of a non-viral liver infection. People above 60 years old and with underlying diseases like diabetes mellitus, cancer or immunodeficiency are more vulnerable to developing non-viral liver infections. Men are twice more likely to be affected than women. Polycystic liver disease also poses a risk of developing non-viral liver infections.

Cause 

Bacteria, fungi or parasites can cause non-viral liver infections. Liver abscesses are mainly caused by anaerobic bacteria, Klebsiella pneumoniae, amoeba and the Echinococcus tapeworm. Anaerobic bacteria and Klebsiella pneumoniae mainly originate from an abdominal focus, such as appendicitis or diverticulitis, and enter the liver via the portal vein. Amoeba and Echinococcus tapeworm enter the body through contaminated water or food. They can reside in the gut for a long time before migrating to the liver. A liver abscess is a newly formed cavity that is pyogenic, i.e., filled with pus of parasites. In polycystic liver disease, a pre-existing cyst may become infected. An immune response from an infection or auto-immune disease causes granulomatous hepatitis. Granulomatous hepatitis can be caused by Mycobacterium tuberculosis, rickettsiae, fungi, schistosomiasis, Leishmania and malaria.

Diagnosis

In liver abscesses, laboratory examination shows raised inflammation parameters, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and leukocytes. The transaminases AST and ALT may vary from normal to (slightly) increased. The location, number and size of liver abscesses can be determined via ultrasound or a CT scan. Roughly 50% of the patients have a positive blood culture. A culture of the abscess obtained by abscess drainage, as part of the diagnostic process or treatment, will allow for identifying the microorganism. An ultrasound or a CT scan will show hepatomegaly, diffuse inhomogeneous liver appearance or focal lesions. When a liver biopsy is performed, epithelioid and gigantocellular granulomas with central necrosis can be seen.

Treatment

In case of liver abscesses, antibiotics that are effective against anaerobic and gram-negative bacteria should be started immediately after taking blood and abscess fluid cultures. If amebiasis is suspected, metronidazole should be added. When cultures show microorganism(s) that are responsible for the infection, antibiotic therapy should be adjusted. Antibiotic therapy usually lasts several weeks. Abscess drainage is almost always performed, except when small abscesses are present. When there is no more spontaneous pus discharge, it is advised to flush the drain twice a day. Before removing the drain, an ultrasound should be performed to ensure that the abscess is entirely resolved. Echinococcal abscesses are surgically removed in combination with oral albendazole for one month. Since most of the microorganisms responsible for the abscess originate from somewhere else in the digestive tract, an underlying cause like appendicitis or diverticulitis should be excluded. In case of granulomatous hepatitis, the causing microorganism should be determined before starting treatment.

Prognosis 

Mortality of non-viral hepatitis increases when complications occur as a result of the infection or treatment, and can be as high as 12%.

Alcoholic Hepatitis

Key points

• Depending on the duration and severity of chronic alcohol use, the following liver damage can occur: steatosis (fatty liver), alcoholic hepatitis or cirrhosis.
• A fatty liver (steatosis) is reversible in case of an alcoholic liver disease; cirrhosis is not.
• The transaminase AST is more elevated than ALT.
• Imaging tests demonstrate fatty infiltrations in the liver in both steatosis and alcoholic hepatitis.

General 

Long-term excessive alcohol consumption can severely damage the liver, resulting in a fatty liver, i.e., steatosis, alcoholic hepatitis and eventually cirrhosis. Excessive alcohol consumption is defined as an oral intake of 80 g of alcohol per day in men and 40 g of alcohol per day in women. It is estimated that in the United States, 7-8% of the population meets the criteria for alcohol abuse as described above.

Epidemiology

Not everyone who excessively consumes alcohol gets diagnosed with hepatic problems. Steatosis is seen in approximately 40% of all moderate alcohol consumers. In heavy drinkers, it is very commonly seen. Only 20% of all heavy drinkers will be diagnosed with alcoholic hepatitis. Approximately 10-20% of alcohol abusers will develop liver cirrhosis. 

Symptoms 

The clinical features of alcoholic hepatitis vary in degree. Steatosis is usually asymptomatic. The liver may be enlarged and smooth on physical examination but not painful. In moderate alcoholic hepatitis, the patient may experience mild jaundice, fatigue, anorexia and weight loss. Severe alcoholic hepatitis is characterized by deep jaundice, ascites, peripheral oedema, fever and sometimes encephalopathy. In addition, abdominal pain is frequently present due to hepatomegaly and splenomegaly.

Cause 

Ethanol is metabolized by the liver. In heavy drinkers the synthesis of fatty acids is altered (increased) as a result of extensive ethanol metabolism. These fatty acids accumulate in the liver cells, but do no damage to the cell. They disappear when alcohol consumption is stopped. 

In alcoholic hepatitis, polymorphonuclear leukocytes also infiltrate liver parenchyma. This causes damage to liver cells. Necrosis of hepatocytes also occurs and is caused by oxidative stress due to enhanced TNF-alpha production by hepatic macrophages. The severity of the damage ranges from mild liver failure, e.g., asymptomatic derangement of biochemistries, to severe liver failure.

In cirrhosis, normal hepatic parenchyma is replaced by fibrous tissue and regenerative nodules, as can be read under ‘Liver Cirrhosis’. It is not completely clear why some individuals progress from steatosis to more advanced stages of liver disease, like alcoholic hepatitis or cirrhosis. Susceptibility may be elevated due to genetic factors. 

Diagnosis

A positive history of alcohol abuse increases the likelihood of an alcoholic hepatitis. An elevated mean corpuscular volume (MCV), with or without anemia, can indicate heavy drinking. The same applies to thrombocytopenia and an elevated gamma-GT. 

In steatosis, liver biochemistry shows mild abnormalities. Particularly AST and ALT levels are slightly elevated with a maximum of 2 times the upper limit of normal. In patients without alcoholic liver problems, the AST:ALT ratio should be <1. An AST:ALT ratio >2 is strongly suggestive of alcoholic liver disease. 

In alcoholic hepatitis, the severity of liver biochemistry abnormalities ranges from mild to severe, in congruence with the symptoms. Besides levels of AST and ALT, serum bilirubin, AP and prothrombin time may also be elevated. In addition, leukocytosis, an elevated CRP level, and low serum albumin can also be found in alcoholic hepatitis.

An ultrasound, CT scan with contrast or MRI can demonstrate fatty infiltrations of the liver in both steatosis and alcoholic hepatitis. A liver biopsy usually demonstrates fatty deposits when steatosis is present. In addition, inflammation and necrosis are seen in alcoholic hepatitis.

Treatment

Abstinence from alcohol and adequate nutritional support, e.g., sufficient intake of proteins and vitamins, remain cornerstones of managing patients with alcoholic hepatitis. Steatosis and mild alcoholic hepatitis resolve spontaneously when alcohol consumption is stopped. Damage from severe alcoholic hepatitis and liver cirrhosis is irreversible, but by discontinuing alcohol consumption, further deterioration can be prevented.

The use of steroids after being diagnosed with alcoholic hepatitis is controversial but is sometimes applied in patients with severe alcoholic hepatitis accompanied by encephalopathy.

Prognosis 

Without alcohol cessation, the prognosis of alcoholic hepatitis is poor. Patients with advanced alcoholic hepatitis may have a 5-year survival rate of 15%. Of the patients with severe alcoholic hepatitis, 40% die within 6 months after the onset of the clinical syndrome. Patients with deep jaundice or hepatic encephalopathy at the time of presentation have an even poorer outcome.

Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Key points

• In non-alcoholic fatty liver disease, the liver contains fatty deposits without signs of inflammation; AST and ALT are mildly elevated.
• In non-alcoholic steatohepatitis, the liver also shows signs of inflammation and AST and ALT are increasingly elevated.
• Non-alcoholic steatohepatitis can progress into hepatic cirrhosis.
• The prevalence is proportional to levels of obesity and diabetes mellitus.
• Weight loss is key when treating patients with non-alcoholic liver disease and steatohepatitis.

General

Non-alcoholic fatty liver disease (NAFLD) is a form of chronic hepatitis that has histologic features similar to alcohol-induced hepatitis. However, NAFLD is only found in patients without a history of alcohol abuse. This disease is characterized by fat accumulation in the liver, i.e., hepatic steatosis, and can progress from mild steatosis into steatohepatitis, advanced fibrosis, cirrhosis, and eventually hepatic failure. NAFLD is an umbrella term for non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). 

Epidemiology

The prevalence of NAFLD is increasing in conjunction with rising prevalence rates of obesity and diabetes mellitus in Western nations. Approximately 20 to 30% of the US population has NAFLD. In addition, approximately 20 to 30% of all NAFL patients develop NASH, and of all people with NASH, 5 to 12% will progress into cirrhosis.

Symptoms 

Most patients with NAFL are asymptomatic, with the disease mainly discovered incidentally, for example, on routine laboratory examination. Patients at an advanced stage of NASH may experience abdominal pain in the left upper quadrant. When cirrhosis or liver failure has occurred, patients may experience ascites, oedema, jaundice, muscle weakness and fatigue.

Risk factors 

The risk of developing NAFLD is significantly increased in obese patients. Approximately 40% of all patients with NAFLD are obese. Diabetes mellitus, insulin resistance, hypertriglyceridemia and other metabolic syndromes have been shown to predispose individuals to NAFLD.

Cause 

NAFLD is caused by a disruption of the fat- and glucose metabolism, which causes fat to accumulate in the liver. Fat accumulation is a reversible process. It is not fully understood why some obese people develop NAFLD and others do not. It also remains unrevealed why some patients with NAFL develop NASH and others do not, although older people seem to be more at risk.

Figure 4. Overview of the multifactorial pathogenesis of non-alcoholic fatty liver, wherein genetic predisposition, obesity, insulin resistance, lipotoxicity, inflammation, bile salts, the microbiome of the gut, and nutrition play a role. Note that not all processes are included in the scope of this chapter. FGF19 = fibroblast growth factor 19; FXR = farnesoid X receptor; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide; LPS = lipopolysaccharide; VLDL = very low-density lipoprotein. Images courtesy of NTVG.

The diagnosis of NAFLD is often suspected when routine laboratory tests (i.e. AST and ALT) show abnormal liver biochemical tests or imaging tests show hepatic steatosis or hepatomegaly. 

NAFLD should be diagnosed only in people who drink little or no alcohol and if other causes of liver disease, including viral hepatitis, auto-immune hepatitis or drug-induced liver disease, are excluded.

In NAFL, ALT and AST are usually mildly elevated. In NASH, the increase of ALT and AST levels is more pronounced. Glucose, triglycerides and cholesterol should be examined in obese patients when NAFLD is suspected. Raised serum ferritin levels can indicate an iron overload disorder, which can disrupt insulin functionality and cause NAFLD.

Imaging modalities, including ultrasonography, CT and MRI can be used to demonstrate fat accumulation in the liver. In addition, these imaging techniques should be used to detect signs of cirrhosis. 

A liver biopsy is often needed to confirm the diagnosis of NASH and stage the degree of fibrosis and inflammation. However, a biopsy is often not indicated when the only abnormality is hepatic steatosis based on imaging and aminotransferases are normal.

Histological coupes of 2 different liver biopsies. (a) Simple steatosis is characterized by the accumulation of fatty tissue between the hepatocytes without the properties of cell damage (HE-stain, x20). (b) Non-alcohol steatohepatitis is characterized by steatosis, hepatocyte swelling (‘ballooning’), and lobular inflammation (HE-stain, x20). Images courtesy of NTVG.

Treatment

Since NAFLD is mainly caused by obesity and insulin resistance, losing weight is the first step in treatment. A healthy diet and exercise contribute to fat reduction. Both biochemical and histological improvement is seen in patients who lose weight. A liver transplant is only indicated in patients with advanced cirrhosis or liver failure.

Prognosis 

If a patient can lose weight and resolve insulin resistance, NAFL is reversible and can dissolve without residual symptoms. In NASH, hepatitis may also be cured, but fibrosis of cirrhosis can not. If NAFLD is undiscovered or left untreated, steatosis can progress into fibrosis, cirrhosis and eventually liver failure.

Drug or Toxin-Induced Hepatitis

Key points

• Drug or toxin-induced hepatitis mostly affects female and elderly patients, as well as patients with a history of liver disease.
• Damage is caused through the accumulation of toxic metabolites, interference with canalicular bile pumps or activation of the immune system.
• A liver biopsy may be helpful when the cause of hepatitis is unclear.

General 

Hepatitis can be caused by the exposure to certain medications or toxins. The onset of this type of hepatitis can arise insidiously after taking chronic medication or acutely in case of an overdose. Usually, the amount of drugs or toxins relates to the damage to the liver. This amount must be above a certain threshold that differs per drug or toxin. 

Epidemiology

Hepatitis caused by drugs or toxins is rare, but is the most common cause in all patients with acute liver failure.

Symptoms 

The clinical features of drug or toxin-induced hepatitis vary in degree. In mild cases, the patient may have no to few symptoms. In moderate hepatitis, the patient may experience mild jaundice, fatigue, anorexia and weight loss. Severe drug or toxin-induced hepatitis is characterized by deep jaundice, ascites, peripheral oedema, fever and liver failure. In addition, abdominal pain is frequently present due to hepatomegaly.

Risk factors 

Some people are more susceptible to drugs or toxin-induced hepatitis, e.g., people with a history of liver disease, women and the elderly. Taking drugs and alcohol at the same time or the use of herbal supplements alongside medication can also contribute to the development of drug-induced hepatitis.

Cause 

There are many ways in which a drug or toxin can cause damage to the liver: by toxic metabolites released from the metabolism of the drug or toxin, by interference with canalicular bile pumps, or through activation of the immune system. The metabolism of drugs mainly occurs in the liver. Drugs must be converted from fat-soluble drugs to water-soluble compounds that can be excreted in bile or urine. Under normal circumstances, toxic metabolites of this process are immediately detoxified by glutathione. Acute or chronic Ingestion of large amounts of drugs or toxins, or a combination of small amounts or different hepatotoxic drugs or toxins, may lead to depletion of glutathione. This depletion leads to the accumulation of toxic metabolites and damage to liver cells. In Western countries, this mechanism is commonly seen in the intoxication with acetaminophen (paracetamol). Normally, acetaminophen is broken down into effective conjugates and the toxic side-product NAPQI in the liver. NAPQI is usually conjugated into a non-toxic form by glutathione. However, when acetaminophen is consumed in large quantities, the body runs out of glutathione, and the toxic NAPQI accumulates, resulting in hepatotoxicity. Treatment consists of the administration of N-acetylcysteine, a precursor of glutathione, to replenish the body’s reserves.

A drug or toxin, or its metabolites, can interfere with canalicular bile pumps, leading to endogenous bile acid accumulation and damage to liver cells. This is called cholestatic toxic hepatitis. The binding of toxic metabolites to liver proteins can alter the antigenicity of liver cells. This can stimulate the activation of the immune system and the production of antibodies against liver cells. This is called indirect hepatotoxicity.

Type of drug	Examples
Analgesia	Acetaminophen (paracetamol) NSAIDs
Antibiotics	Fluoroquinolones (levofloxacin/ofloxacin) Macrolides (azithromycin, erythromycin, telithromycin) Penicillines (amoxicillin-clavulanate, flucloxacillin, oxacillin) Sulfonamides (cotrimoxazol, trimethoprim-sulfametrol) Other (nitrofurantoin)
Anti-epileptics	Phenytoin Phenobarbital Carbamazepine Valproic acid (rare)
Hormonal	Anabolic steroids Oral contraceptives
Statins	Atorvastatin Simvastatin
Herbal medicines	e.g., Ephedra, Germander, Pennyroyal.

Table 1. Overview of a selection of commonly used hepatotoxic drugs.

Diagnosis

In case of an acute drug or toxin-induced hepatitis, the (hetero)anamnesis is most important. Therefore, besides medication on prescription, one also should ask about use of over-the-counter drugs, herbal supplements, home-picked berries, and mushrooms.

The diagnosis of late-onset drug or toxin-induced hepatitis is usually more complex and often made by the exclusion of other causes. Chronic medication is not always recognized as the cause of hepatitis.

Laboratory research may show hyperbilirubinemia and elevated liver enzymes, mainly AST and ALT in hepatitis caused by toxic metabolites and immune system activation, mainly gamma-GT and AP in cholestatic toxic hepatitis. Low albumin levels and a prolonged prothrombin time indicate a diminished liver function in severe cases. 

A liver biopsy is not always necessary but can be helpful, especially in cases where the cause of hepatitis is unclear. A liver biopsy showing portal tract neutrophils and hepatocellular cholestasis suggest drug or toxin-induced injury. 

Treatment

The first step in treating drug or toxin-induced hepatitis is to remove the toxin or drug that is causing hepatitis. The second step is supportive treatment. Depending on the degree of inflammation and damage, hepatitis can resolve spontaneously without residual symptoms or, in severe cases, can be life-threatening. A liver transplantation may be necessary.

In case of hepatitis caused by an acetaminophen overdose, the administration of N-acetylcysteine reduces the severity of hepatic necrosis. However, in almost all other cases, there is no specific antidote.

Prognosis 

Continuing the drug or prolonged exposure to the toxin that causes hepatitis will result in severe damage to the liver or even liver failure.

Auto-Immune Hepatitis

Key points

• Auto-immune hepatitis mostly affects women; its peak incidence is at the age of 15 to 25 and 40 to 65.
• Auto-immune hepatitis develops through the interplay of genetic predisposition and environmental triggers.
• Auto-immune hepatitis is often accompanied by a hypergammaglobulinemia, specifically an increase of IgG.
• Treatment consists of corticosteroids for at least one year.
• The chance of relapse is 90%, but the prognosis is good if auto-immune hepatitis is adequately treated.

General 

Auto-immune hepatitis refers to a chronic and progressive inflammation of the liver caused by the activation of the immune system. It is thought that an unknown exogenous factor triggers this inadequate immune response. 

Epidemiology

The worldwide incidence of auto-immune hepatitis is approximately 1 to 2 per 100.000 individuals. Auto-immune hepatitis is more common among individuals of Northern European ancestry. Women appear to be affected more than men. There is a peak incidence at the age of 15 to 25 years and 40 to 65 years. Patients treated with immunotherapy for cancer have a 2 to 4% chance of developing auto-immune hepatitis. Since the use of these kinds of treatment is rapidly growing, the expectation is that the incidence of auto-immune hepatitis will increase over the next few years.

Symptoms 

The clinical presentation of hepatitis may vary in severity, from an asymptomatic elevation of liver enzymes to fulminant hepatitis. The most common features of auto-immune hepatitis are fatigue, malaise, jaundice, abdominal pain due to hepatomegaly, and sometimes arthralgias. In fertile women, amenorrhoea is often seen. On physical examination, jaundice can be seen, the liver – especially the left lobe – may be enlarged and stigmata like spider naevi may be present.

Risk factors 

Patients with HLA haplotypes HLA-DR3 and HLA-DR4 have a higher risk of developing auto-immune hepatitis. In 25 to 40% of the cases, patients or a first-degree family member have another auto-immune disease, like type 1 diabetes mellitus, celiac disease, rheumatoid arthritis or thyroiditis. 

Cause 

The proposed mechanism for developing auto-immune hepatitis is thought to be the interplay of genetic predisposition and environmental triggers. In some cases, auto-immune hepatitis is provoked by a viral infection, such as hepatitis A, Epstein-Barr or measles, or drugs or toxins, such as nitrofurantoin, minocycline, hydralazine, methyldopa or infliximab. 

Like in other auto-immune diseases, women have a higher risk of developing auto-immune hepatitis in the first year postpartum. The mechanism is not entirely understood, but it is thought that hormonal and immune-related shifts that occur during and after pregnancy play a significant role.

Immunotherapy used in cancer treatment, like CTLA-4 inhibitors and PDL-1 inhibitors, is another cause of auto-immune hepatitis. This immunotherapy aims to stimulate the immune system to destroy cancer cells. However, when this immune reaction is directed against cells other than cancer cells, for example, hepatocytes, it may cause an auto-immune inflammation. This phenomenon is described as ‘immune-related adverse effects’.

Diagnosis

Diagnosing auto-immune hepatitis is usually not easy. It is based on a combination of clinical, laboratory and histological findings and the exclusion of other causes of hepatitis.

Like in almost all types of hepatitis, laboratory examination shows a typical elevation of the transaminases AST and ALT. In addition, bilirubin, AP and gamma-GT levels may vary between normal to (slightly) elevated. The liver function can decrease, resulting in a lower albumin level and a prolonged prothrombin time. Thrombocytopenia can occur due to hypersplenism and portal hypertension or antibodies directed against the platelets. Hypergammaglobulinemia is often seen, particularly elevated serum immunoglobulin G (IgG) levels. Antibodies directed against nuclear factor (ANF), smooth muscle (SMA), liver microsomes and cytoplasm are present in most cases.

A liver biopsy supports the diagnosis, but a liver biopsy alone is not sufficient. Interface hepatitis on histologic examination is a hallmark of auto-immune hepatitis, showing dense lymphoplasmacellular infiltration in portal tracts extending into the liver lobules. Hepatocellular rosettes represent a regenerative response to the necro-inflammatory damage. They are seen in 50% of all liver biopsies. In severe cases of auto-immune hepatitis, lobular changes are dominated by necrosis; in chronic cases, fibrosis can be present.

Figure 5. Histopathological hallmarks of auto-immune hepatitis with (a) interface hepatitis with lymphoplasmacellular infiltrates (HE-stain, x175), (b) plasma cells in an area with interface hepatitis (HE-stain, x200), severe auto-immune hepatitis: there are only a few areas with parenchyma left (green). Otherwise, the tissue is inflamed or necrotic (HE-stain, x5). Images courtesy of NTVG.

Treatment

Treatment with corticosteroids is the cornerstone of treating auto-immune hepatitis. In most cases, complete remission is achieved. Remission occurs when the patient is asymptomatic with normalization of transaminases, inflammatory markers, gammaglobulin and (in case of multiple liver biopsies) histological improvement.  Although the patient may quickly notice the decrease in symptoms, corticosteroid therapy must last for at least one year. After that, the dosage can be gradually reduced for at least one year. By adding azathioprine to control hepatitis, the corticosteroid dose can be reduced. This reduction lowers the chance of long-term side effects.

The chance of getting a relapse of symptoms can be as high as 90% within the first 3 years of remission. Relapses can be treated similarly to auto-immune hepatitis on initial presentation, followed by a maintenance dose of corticosteroids. 

If auto-immune hepatitis is caused by immunotherapy given to cancer patients, immunotherapy must be halted and corticosteroids should be administered.

Prognosis 

Untreated auto-immune hepatitis can lead to liver cirrhosis and liver failure. The risk of death secondary to liver failure is elevated in patients under 20 or over 60 years of age.

With the treatment of auto-immune hepatitis with corticosteroids, patients can have an average life expectancy without relapses.

Hepatic Cirrhosis

Key points

• In hepatic cirrhosis, functional liver tissue is replaced by fibrotic scar tissue and regenerative nodules.
• On examination, patients might have jaundice, ascites and oedema. The liver might be small and irregular on palpation. 
• Levels of the transaminases AST and ALT, and bilirubin are usually elevated.
• A liver biopsy is the gold standard for diagnosing hepatic cirrhosis.
• Complications include ascites, jaundice, and varices in the upper gastrointestinal tract.
• Treatment focuses on preventing further fibrosis and reducing the risk of complications.

General 

Cirrhosis develops after chronic inflammation, resulting in the replacement of liver tissue with fibrotic scar tissue and regenerative nodules. Progressive loss of liver function is observed due to changes in the liver’s regular lobular organization. Complications resulting from liver cirrhosis are ascites, jaundice or esophagogastric variceal bleeding. The presence of any of these complications points towards decompensated liver cirrhosis. The classification of cirrhosis is based on etiology, size of hepatic nodules and whether there is compensation of the cirrhosis.

Epidemiology 

Liver cirrhosis is a relatively common complication of underlying liver disease. Approximately 10 to 20% of alcohol abusers develop liver cirrhosis, and approximately 5 to 12% of people with non-alcoholic steatohepatitis, also known as NASH, will progress into cirrhosis.

Symptoms

Liver cirrhosis develops slowly. Patients may be asymptomatic or have only minor complaints in the initial stage. At an advanced stage, patients usually present with variable signs and symptoms ranging from fatigue and weakness to nausea, weight loss, and abdominal pain. In severe cases, ascites, oedema, jaundice, pruritus and esophagogastric variceal bleeding are found.

Cause

Liver cirrhosis is a result of chronic inflammation. The most common causes of this chronic inflammation are viral infections, toxins, alcohol abuse, hereditary conditions, or auto-immune disease. Regardless of etiology, the effect on the liver is mostly the same; functional liver tissue is replaced by fibrous scar tissue and regenerative nodules. 

Affected organ	Cause
Liver	Micronodular*	Alcohol, non-alcoholic steatohepatitis (NASH), drugs, toxins
	Macronodular*	Chronic hepatitis B or C infection, auto-immune hepatitis, unknown (cryptogenic cirrhosis)
Biliary tract	Primary biliary or sclerosing cholangitis, secondary biliary cirrhosis

Table 2. Common causes are categorized and listed.

Diagnosis

A combination of tests is usually needed to diagnose liver cirrhosis.

Findings of physical examination may be jaundice, ascites and oedema.The liver is often not palpable because it is reduced in size (shrunken). Laboratory findings may show mild to moderately elevated AST, ALT and progressively increasing bilirubin. In addition, depending on the degree of liver cirrhosis, low albumin levels, prolonged prothrombin time, anemia, and thrombocytopenia may be found.

A liver biopsy is the gold standard for diagnosing liver cirrhosis but only has a sensitivity of 60-70%. Active bridging fibrous septa and parenchymal nodules bearing a mixture of replicating and senescence hepatocytes are pathognomonic of liver cirrhosis. A biopsy might reveal the underlying cause of cirrhosis based on liver tissue containing uniform nodules (micronodular) or larger nodules (macronodular) (see table 2). 

Imaging modalities such as ultrasound, contrast-enhanced CT, MRI, and transient elastography (via FibroScan) help diagnose cirrhosis. Furthermore; liver size, the presence of hepatic nodules and the presence of ascites should be examined. Finally, Esophagogastroduodenoscopy should be performed to demonstrate or exclude varices in the upper gastrointestinal tract. Additional diagnostics, such as serology and PCR techniques for viral hepatitis and auto-immune antibodies, can be deployed to determine the underlying cause of liver cirrhosis further. 

The Child-Pugh classification and MELD classification (MELD stands for ‘Model for End-Stage Liver Disease’) are used to determine the severity of cirrhosis. The higher the score, the more severe the liver cirrhosis and the lower the life expectancy. 

The Child-Pugh score is based on laboratory findings, i.e., bilirubin, albumin and INR, ascites and encephalopathy.  The MELD classification determines which patient qualifies for a liver transplant. This score is based on laboratory findings, i.e., bilirubin, creatinine, sodium and INR, and whether the patient is receiving intermittent hemodialysis or continuous venovenous hemodialysis (CVVHD).

Parameter	Score
	1	2	3
Bilirubin	< 2mg/dL	2 – 3mg/dL	> 3mg/dL
Albumin	> 3.5 g/dL	2.8 – 3.5 g/dL	< 2.8 g/L
INR	< 1.7	1.7 – 2.2	> 2.2
Ascites	None	Mild	Moderate
Encephalopathy	None	Grade 1-2	Grade 3-4
Score	5-6 Grade A	7-9 Grade B	≥10 Grade C
2-year survival	65-100%	60-80%	35-45%

Table 3. The Child-Pugh classification

Treatment

Fibrotic scarring causes permanent damage to the liver. Thus, the underlying cause of liver cirrhosis should be managed first. Treatment is aimed at preventing further fibrosis and reducing the risk of complications. Treatment includes avoidance of alcohol, vaccination for HVB and HVC, a balanced diet, weight reduction and early treatment of precipitating factors such as dehydration, hypotension and infection.

The complications of cirrhosis should be managed with targeted therapies; esophageal variceal hemorrhage, ascites, oedema or encephalopathy require urgent resolution.

Liver transplantation is indicated in case of decompensated cirrhosis that does not respond to medical treatment.

Prognosis

Untreated liver cirrhosis eventually leads to liver failure, a lethal condition. Child-Pugh and MELD scores are used during follow-up to detect whether the patient’s condition deteriorates. Patients with cirrhosis must be closely monitored to prevent the development of portal hypertension and hepatocellular carcinoma (HCC).

Hepatic Insufficiency and Failure

Key points

• Hepatic insufficiency or failure is the loss of almost all metabolic, secretory and regulatory liver functions.
• It can be acute, chronic, or acute-on-chronic, but it is always life-threatening.
• Symptoms include gastrointestinal complaints and neurological symptoms. 
• In hepatic encephalopathy, ammonia builds up, and confusion, disorientation and coma can occur.
• Liver transplantation is the last-resort treatment option.
• Hepatic failure has a mortality rate of 80 to 100%.

General 

Hepatic insufficiency, also known as liver failure, represents the loss of almost all metabolic, secretory and regulatory liver functions. This results, for example, in the accumulation of waste products, drugs and toxins, a decrease in the production of albumin and blood clotting factors and disturbed glucose management. Liver failure can be classified as acute, chronic or acute-on-chronic, but it is always life-threatening.

Epidemiology

Acute liver failure is a rare condition with an incidence of approximately 1 to 10 cases per million people annually, and is more common in men than in women.

Symptoms

Fatigue, nausea, vomiting and abdominal pain are common symptoms of liver failure. Jaundice can be present or absent. The accumulation of ammonia leads to hepatic encephalopathy, with symptoms like apathy, drowsiness, confusion and flapping tremor. Hepatic coma and epileptic insults may also occur.

Risk factors

Chronic, underlying liver disease is a risk factor for developing liver failure.

Cause

There are numerous causes of liver failure, of which alcoholic, auto-immune or viral hepatitis, intoxication with acetaminophen or mushrooms, or impaired blood flow – due to an infarction or Budd-Chiari syndrome – are most common. In 15 to 25% of all adults with liver failure, the cause cannot be determined.  

Diagnosis

Based on symptoms and physical examination findings, liver failure may be suspected, like tender abdomen, hypotension, ascites, peripheral oedema, palmar erythema and spider naevi. In hepatic encephalopathy, confusion, reduced consciousness and flapping tremor are seen.

Laboratory evaluation is required to evaluate severity. Typically, the prothrombin time is prolonged, serum aminotransferases AST and ALT levels are elevated, albumin levels are reduced, and bilirubin and ammonia levels are elevated.

An ultrasound or CT scan can be used to determine liver size and aspect, the presence of ascites, and the presence of splenomegaly.  A liver biopsy is usually not necessary to diagnose liver failure; it is contraindicated because ascites and impaired blood clotting may cause major bleeding. If the underlying liver disease is unknown, laboratory research and imaging should focus on diagnosing the underlying condition.

Treatment

The first goal in treating liver failure is to stabilize the patient by supplying intravenous fluids, clotting factors, glucose and albumin. Treatment of liver failure should also be aimed at eliminating or reducing the underlying cause. In case of hepatic encephalopathy, ammonia production should be reduced by preventing the absorption of proteins from the gastrointestinal tract. This can be achieved by ceasing the consumption of oral proteins, e.g., meat and dairy, and by orally or rectally administering lactulose. Liver transplantation is the last-resort treatment option. However, the transplantation of a liver is a major operation with a high risk of complications. In addition, as the global demand for livers exceeds the supply, this option is not available to everyone.

Prognosis

Liver failure is a life-threatening disorder. Untreated, the mortality rate is 80 to 100%. The mortality rate after liver transplantation is 60%.

Vascular Disorders of the Liver

Portal Hypertension

Key points

• Insufficient venous drainage because of diffuse obstruction and congestion of the sinusoids results in portal hypertension.

• Portal hypertension is a complication of an underlying liver disease and is defined as a pressure gradient over 6 mmHg between the portal and hepatic vein.

General 

Portal hypertension is the permanent increased pressure within the portal venous system. It is characterized by a pressure gradient of 6 mmHg or more between the portal and hepatic vein. A pressure gradient greater than 10 mmHg is clinically significant. Collateral blood vessels are formed to reduce the pressure of the portal venous system. These collaterals drain blood into the systemic venous circulation, i.e., portosystemic shunting. Splenomegaly and esophageal varices are common complications of portal hypertension.

Symptoms 

Increased pressure in the portal venous system itself does not lead to any complaints. However, the consequences of increased pressure do. In addition, symptoms of the underlying condition are often present. Patients with portal hypertension may experience abdominal pain due to hepatomegaly, splenomegaly, a significant amount of ascites or portal thrombosis. Esophageal varices can easily bleed and cause hematemesis or melena.

Cause 

The etiology of portal hypertension can be classified as either prehepatic, intrahepatic, or post-hepatic. Pre-hepatic portal hypertension is the obstruction or disruption of blood flow before blood enters the liver. Most commonly, this is due to a portal vein or splenic vein thrombosis or a neoplasm that compresses these blood vessels. 

Intrahepatic causes of portal hypertension encompass 95% of all portal hypertension causes. Increased vascular resistance is caused by cirrhosis or fibrosis, leading to decreased blood flow through the liver and accumulation of blood in the portal venous system. Posthepatic causes are rare and occur in the bloodstream beyond the liver. Most posthepatic causes are at the level of the hepatic vein, e.g., Budd-Chiari syndrome, inferior vena cava or the heart, e.g., constrictive pericarditis.

Diagnosis

Portal pressure measurement is not needed to diagnose portal hypertension in cases where clinical signs and symptoms are manifested. On physical examination, caput medusae can be seen around the umbilicus or spider angioma on the torso (see Figure 6). The liver may be enlarged, i.e., hepatomegaly, or small, depending on the underlying cause. Splenomegaly is often found.

Figure 6. Left: singular spider angioma encircled in pen on a patient’s torso, image courtesy of Chamberlain. Right: multiple spider angiomas in a patient, image courtesy of wikimedia commons.

There are no diagnostic laboratory findings exclusively associated with portal hypertension. The underlying disease can cause increased liver enzymes, such as AST, ALT, AP and gamma-GT, or decreased liver function, shown by low albumin levels and a prolonged prothrombin time. Thrombocytopenia, leukocytopenia and sometimes anemia can be found due to the sequestration of blood cells in the spleen. Esophageal varices can be identified on gastric endoscopy. In addition, ultrasound can be used to identify portal thrombosis.

Treatment

Management of portal hypertension requires the treatment of the underlying condition. In addition, the complications of portal hypertension should be treated. Anticoagulation therapies can be administered for acute portal vein or splenic vein thrombosis. However, the increased risk of bleeding due to esophageal varices or thrombocytopenia must be observed. A splenectomy can resolve a sizable splenic vein thrombosis with signs of hypersplenism.  

A transjugular intrahepatic portosystemic shunt (TIPS) is an artificial bypass between the portal and hepatic vein, which reduces the pressure in the portal vein. TIPS is mainly used in patients with a significant amount of ascites. To further reduce ascites, a salt-restricted diet and diuretics should be prescribed. Variceal bleeding can be treated with non-selective beta-blockers and endoscopic band ligation. Diagnosis and treatment of esophageal varices can also be found in SECTION… 

Prognosis 

The prognosis depends on the underlying etiology of portal hypertension.

Budd-Chiari Syndrome

Key points

• Budd-Chiari syndrome is a rare condition caused by insufficient venous drainage resulting from focal or diffuse obstruction in the intrahepatic or extrahepatic veins. 
• Acute Budd-Chiari syndrome comes with a classic triad of symptoms: abdominal pain, ascites and hepatomegaly.
• Budd-Chiari syndrome usually has a subacute onset, but may be chronic or progress into liver failure.

General 

Budd-Chiari syndrome refers to the occlusion of the hepatic vein or inferior vena cava, causing congestion of blood in the hepatic venous system, which can eventually lead to portal hypertension (see ‘Portal Hypertension’). Budd-Chiari syndrome can be acute or chronic, fulminant or asymptomatic. The subacute type of Budd-Chiari syndrome is the most common. Eventually, it may become chronic and progress into fulminant liver failure. 

Epidemiology

Budd-Chiari syndrome is rare. It affects women slightly more often than men. Clinical manifestations of Budd-Chiari syndrome usually develop between the second and fourth decade of life.

Symptoms 

Acute Budd-Chiari syndrome presents with the classic triad of abdominal pain, ascites and hepatomegaly. The enlargement of the liver and stretching of the liver membrane causes abdominal pain. Ascites arise due to increased vascular pressure. Peripheral oedema can also occur.

Cause 

Conditions that increase blood coagulability, such as hematologic disorders, coagulopathies, chronic inflammatory diseases, pregnancy or use of oral contraceptives, are risk factors for developing Budd-Chiari syndrome. Most cases of hematologic origin are provoked by JAK2-associated myeloproliferative neoplasms, polycythemia vera and essential thrombocytosis. Furthermore, compression from outside the liver on the hepatic vein or inferior vena cava, e.g., by a tumor of fibrosis, may cause Budd-Chiari syndrome.

Diagnosis

Budd-Chiari syndrome is diagnosed using an ultrasound, CT scan or MRI. Sometimes the hepatic vein thrombosis can be visualized. In other cases, the obstruction can be hard to find on radiologic images. However, ascites, an enlarged caudate lobe, prominent azygos and hemiazygos veins, spontaneous intrahepatic anastomoses, or hepatomegaly can be found and are highly suggestive of Budd-Chiari syndrome. 

A liver biopsy should be used when imaging studies fail. Acute Budd-Chiari syndrome may show high-grade venous congestion, centrilobular liver cell atrophy and sometimes thrombi in the terminal hepatic venules. Fibrosis with large nodules and lobes is characteristic of chronic Budd-Chiari Syndrome. 

Treatment

Medical therapy should be aimed at symptom relief and treatment of the underlying disorder. Anticoagulation therapies must be maintained for a lifetime, although this can be associated with undesirable side effects such as bleedings. Surgical thrombectomy, or percutaneous transluminal angioplasty with or without stent placement, is recommended for patients with occlusion of the hepatic vein, patent inferior vena cava, and a high risk of developing liver failure.  

Liver transplantation is the last-resort treatment when conservative and interventional therapy fails to prevent liver cirrhosis and progressive liver failure. A low-sodium diet is recommended, as well as diuretics, to control ascites. In addition, transjugular portosystemic shunt (TIPS) is indicated in patients with portal hypertension developing hepatic cirrhosis.

Prognosis

The prognosis depends on the amount of liver cell damage caused by Budd-Chiari syndrome. Patients with adequately treated acute Budd-Chiari syndrome generally have a good prognosis. Without a proper intervention or in chronic cases, Budd-Chiari syndrome will lead to portal hypertension, cirrhosis and liver failure. Patients will have a high mortality rate. Adverse prognostic factors are associated with older age at diagnosis, elevated serum creatinine and bilirubin levels, and prolonged prothrombin time. 

Benign Tumors in the Liver

Key points

• Benign tumors in the liver are most commonly cysts but can also be hemangiomas, adenomas or focal nodular hyperplasia.
• Benign tumors are more prevalent in women than in men. Hormonal involvement is proven in hemangioma and adenoma, and suspected in focal nodular hyperplasia.
• Most benign tumors are asymptomatic and do not require treatment.
• Cysts and adenomas can transform into malignancies and require close monitoring or preventive resection.

Hepatic Cyst / Polycystic Liver Disease

General 

Simple hepatic cysts are the most frequent manifestation of benign tumors in the liver. Cysts contain clear fluid and can vary from a few millimeters to more than 10 centimeters in diameter. A hepatic cyst can appear solitary, or multiple cysts are present. 

Epidemiology

About 2 to 20% of the World population has hepatic cysts, which they may or may not be aware of. Hepatic cysts are most prevalent in the female population, and their incidence is associated with increasing age. In addition, hepatic cysts are seen in 40% of all patients with autosomal dominant polycystic kidney disease (ADPKD).

Symptoms

Cysts are usually small and asymptomatic, but larger cysts can be associated with severe complications, such as hemorrhage, rupture, infection or compression of the biliary tree. When simple hepatic cysts grow large enough to cause symptoms, nonspecific abdominal pain, nausea, and anorexia are common manifestations. Significantly large cysts may even be palpable on abdominal examination. Despite extensive disease, however, liver function is rarely impaired.

Cause

The cause of simple hepatic cysts is often not known. Hepatic cysts can be congenital but also develop later in life. In case of multiple cysts, an inherited disorder like PCLD or ADPKD (both associated with mutations in PKD1 (16p13.3) and PKD2 (4q21)) should be considered. Cysts can also occur because of dilation of the bile ducts, e.g., in hereditary Caroli’s disease. An echinococcal infection is a common cause of hepatic cysts in non-Western countries. Contaminated water or food may contain eggs. Inside the intestine, larvae hatch from the eggs and migrate to the liver. These larvae turn into bladder worms. After that, blisters with fluid are formed around the bladder worm, creating a cyst. These cysts are also known as hydatid cysts.

Diagnosis

Hepatic cysts are generally found incidentally on radiological images. An ultrasound is the most practical diagnostic modality to confirm the presence of hepatic cysts. It can generally differentiate a simple cyst from a complicated cyst. Radiological and clinical findings confirm the diagnosis; histological confirmation is not necessary. 

Treatment

Asymptomatic, simple hepatic cysts do not require any treatment. While cysts larger than 4 cm in diameter sporadically become malignant, their size and stability should be monitored through ultrasound images. If the cyst is stable for 2 to 3 years, further follow-up is not needed. For patients with symptomatic hepatic cysts, the goal of treatment is to reduce the size of cysts and reduce symptoms while protecting the liver parenchyma. Medical therapy experiments have shown that somatostatin analogues can be efficacious in reducing liver size. In addition, symptomatic hepatic cysts can be treated with percutaneous aspiration, laparoscopic fenestration, or complete cyst excision.

Hepatic Hemangioma

General 

A hepatic hemangioma is a benign liver tumor composed of dilated blood vessels. In most cases, a hemangioma is small and asymptomatic. A hemangioma larger than 4 cm in diameter is a giant hemangioma. 

Epidemiology

A hepatic hemangioma is one of the most common benign liver tumors. About 2 to 4% of all adults have one or more hemangioma(s).

Symptomes

Most hepatic hemangiomas are small, asymptomatic and are found incidentally. However, some may grow large enough to compress surrounding organs and cause symptoms like abdominal pain, dyspepsia, early satiety and vomiting. In giant hemangiomas over 10 to 15 centimeters in diameter, blood circulation disorders can appear, accompanied by fever and night sweats. Common physical examination findings may include a palpable upper abdominal mass or hepatomegaly.

Risk factors 

Common risk factors of developing hepatic hemangiomas are older age, female gender, use of oral contraceptives and pregnancy.

Cause

It is not completely clear what causes liver hemangioma. Genetic mutations probably cause the overexpression of angiogenic factors or the downregulation of angiogenesis inhibitors, which results in the development of a hemangioma. 

Diagnosis

Most hepatic hemangiomas are found incidentally when, for other reasons, an ultrasound, CT scan or MRI is made. A biopsy is rarely necessary to confirm the diagnosis and should be avoided because of a major risk of hemorrhage. Laboratory findings are usually undisturbed because the liver function is usually not affected.

Figure 7. Giant hemangiomas in the liver of a 54-year old female. Preoperative CT scan in the transversal plane. The left liver lobe is almost completely occupied by abnormal tissue, measuring 18 by 11 cm. A similar, hypodense abnormality is visible in the right liver lobe as well. Lower right image: per-operative images from the resected hemangioma. Patient underwent left liver lobe resection due to abdominal pain and because the lesion had been progressively getting bigger.  The lower left image shows the histology of a giant hemangioma in a 30 year old female. It shows widened vascular spaces, separated by narrow strips of connective tissue lined with a singular layer of normal endothelial cells. Images courtesy of NTVG.

Treatment

Treatment of hemangiomas is usually not necessary. However, surgical removal could be considered in large, symptomatic hepatic hemangiomas. In addition, embolization of the hemangioma is an option in patients unfit for surgery or when the hemangioma can not be removed surgically due to its location.

Prognosis 

The prognosis is generally excellent, as most cases do not require medical intervention. 

Hepatic Adenoma

General 

A hepatic adenoma is a benign, well-encapsulated epithelial tumor. Its size varies between a few millimeters to >10 cm.

Epidemiology

Hepatic adenomas are rare. It is most frequently seen in women aged 20 to 50, but men can also be affected.

Risk factors

Hepatic adenomas often occur in women who use oral contraceptives for a more extended period or during pregnancy.  In addition, the chronic use of anabolic steroids and obesity are also associated with the development of hepatic adenoma.

Symptoms

Most adenomas are asymptomatic and are usually discovered by accident. However, pain in the right upper quadrant is the most common complaint in symptomatic patients. When bleeding occurs in the adenoma, the liver may swell, causing (additional) pain. When the capsule around the adenoma tears, hemodynamic instability can occur.

Cause

Estrogens are assumed to play a role in the pathogenesis of hepatic adenomas.

Diagnosis

Most hepatic adenomas are found accidentally when an ultrasound, CT scan or MRI is made for other reasons. On physical examination, the liver may be enlarged and sensitive to palpation. Laboratory findings may be normal in case of a small adenoma or slightly abnormal. A liver biopsy is only performed when there is doubt about whether the lesion is benign or malignant.

Figure 8. On the left an MRI scan of a patient with hepatocellular adenoma of 6cm. Images courtesy of NTVG, 2012). On the right (a) macroscopic coupe of a steatotic adenoma. (b) Immunohistochemical staining of steatotic adenoma, characterizing is loss of staining of the liver type fatty acid binding protein (L-FABP, x50). (c) Macroscopic coupe of inflammatory adenoma. Images courtesy of NTvG.

Treatment 

Cessation of oral contraceptives, anabolic steroids, and weight loss has been shown to cause a partial and complete regression of tumor size. Surgical resection is recommended for all male patients regardless of the tumor size and for women with tumors >5 centimeters because of the risk of bleeding or transformation of the adenoma into a malignant tumor. 

Prognosis

Because of the risks of bleeding and transformation into a malignancy, close monitoring is recommended. The size of the adenoma, its location, and its symptoms determine how often imaging should be repeated. Once women are in the menopause stage, adenomas usually shrink and follow- up can be discontinued.

Focal Nodular Hyperplasia

General 

Focal Nodular Hyperplasia is a benign liver tumor composed of hepatocytes and bile duct cells. The star-shaped core in the center of the tumor is characteristic of FNH.

Figure 9. Intermediate magnification micrograph of focal nodular hyperplasia (H&E stain). Wikicommons.

Epidemiology

Focal nodular hyperplasia is rare. The prevalence ranges from 0,4 to 3% of the general population (worldwide). Women of childbearing age are more frequently affected than men.

Risk factors

Focal nodular hyperplasia is most frequently seen in women at the age of 30-50; a relation between the use of oral contraceptives and FNH is suggested. However, no scientific evidence has been found yet. 

Symptoms

Focal nodular hyperplasia is often asymptomatic and discovered accidentally, as hepatic tumors are usually small. However, some masses may grow large enough to cause symptoms like abdominal pain, dyspepsia, and early satiety, mainly when located in the left liver lobe.

Cause

Focal nodular hyperplasia is believed to originate from congenital abnormalities in the liver blood vessels, causing some parts of the liver to receive more blood, nutrients, and oxygen than other parts. These abnormalities cause these liver cells to grow into a tumor-like mass.

Diagnosis

Focal nodular hyperplasia is usually found incidentally when an ultrasound, CT scan or MRI is made for other reasons. A CT scan depicts a well-circumscribed lesion with a typical central star. Physical examination usually shows no deviations, but hepatomegaly can be noticeable. Laboratory findings (gamma-GT) are usually normal but can be slightly abnormal when focal nodular hyperplasia encompasses larger masses

Treatment

A resection is rarely indicated since most patients with focal nodular hyperplasia experience no symptoms, and hepatic masses do not tend to transform into malignant masses. About 80% of all focal nodular hyperplasias remain their size. About 20% of the tumors increase in size over the years, which could eventually cause symptoms. Regular radiologic follow-up is unnecessary.

Prognosis

Focal nodular hyperplasia is a benign tumor with a low risk of complications, which means that the prognosis is good.

Malignant Tumors in the Liver

Malignant tumors of the liver are classified as primary, i.e., hepatocellular carcinoma, or secondary, i.e., metastatic. 

Hepatocellular Carcinoma

Key points

• Hepatocellular carcinoma remains asymptomatic in early stages, but patients may experience symptoms of underlying cirrhosis and in advanced stages.
• Laboratory findings show deranged liver enzymes and liver function tests due to underlying cirrhosis.
• A liver biopsy should be avoided because of the risk of needle tract seeding. However, in cases of diagnostic uncertainty, it might be unavoidable.
• The curative treatment consists of partial hepatectomy or total liver resection combined with subsequent transplantation.
• The prognosis of hepatocellular carcinoma depends on disease progression at time of diagnosis, tumor size, degree of cirrhosis, and the patient’s condition.

General 

Hepatocellular carcinoma is an aggressive primary malignancy of the liver that most frequently develops in cirrhotic livers. 

Epidemiology

Hepatocellular carcinoma is one of the most common malignant tumors worldwide; it mainly occurs in non-Western countries. Every year, 0,5 to one million people are diagnosed. Males are disproportionately affected, with a higher incidence among men older than 55.

Risk factors

Approximately 75 to 85% of all patients with hepatocellular carcinoma have existing liver cirrhosis. The causes of cirrhosis can be various. However, the most common causes are chronic HVB and HVC infections. 

Symptoms 

In the early stages of the disease, hepatocellular carcinoma itself is asymptomatic, although symptoms of liver cirrhosis and liver failure may be present. The presence of symptoms of liver failure is a poor prognostic sign and is therefore associated with a lower life expectancy. Possible symptoms due to tumor enlargement may manifest as anorexia or abdominal discomfort. Malaise, weight loss and night sweats are common at an advanced stage of hepatocellular carcinoma.

Cause 

Hepatocellular carcinoma may develop as a complication of liver cirrhosis. It arises insidiously from low-grade dysplastic nodules that develop into high-grade dysplasia under chronic inflammation. By integrating with the host’s genome, HBV might cause hepatocellular carcinoma without liver cirrhosis.

Diagnosis

The diagnosis can be made based on a combination of symptoms, laboratory findings, radiological images and histological examination. Laboratory findings show elevation of the liver enzymes AST, ALT, gamma-GT and AP, a prolonged prothrombin time, reduced albumin levels and increased bilirubin levels, indicating a deterioration of the liver function. In addition, mild anemia and thrombocytopenia can be found. Alpha Fetoprotein (AFP) is increased in 50 to 75% of all patients with advanced hepatocellular carcinoma. 

Hepatocellular carcinomas are best visualized with an ultrasound, CT scan with contrast or MRI. A CT scan showing arterial phase hyperenhancement in combination with a rapid washout in tumors over 1 cm typically suggests the presence of hepatocellular carcinoma.

An additional CT scan of the thorax or abdomen should be used to search for metastases, e.g., in lungs, lymph nodes or bones. A liver biopsy is indicated in the absence of cirrhosis and if radiologic findings are unclear. A liver biopsy should be avoided in patients suspected of having hepatocellular carcinoma with a chance of curation because of the risk of needle tract seeding. Histology usually shows a well-differentiated tumor.

Treatment

Curation can only be achieved with a partial hepatectomy or a total liver resection in combination with a liver transplantation. Feasibility of these treatment options depends on tumor size and location and the condition of the remaining liver at the time of diagnosis. Incurable patients can be treated with ethanol injections, chemoembolization, radiotherapy, systemic chemotherapy, and radiofrequency ablation. These treatments aim to diminish symptoms caused by the tumor and prolong the life span.

Prognosis 

Curability of hepatocellular carcinoma depends on tumor size, presence of metastases, degree of cirrhosis and the patient’s condition. In case of curative treatment, i.e., partial hepatectomy or liver transplantation, the 5-year survival is 37 to 56%. The prognosis is poor when palliative treatment or best-supportive care is given. Early detection is crucial for a positive prognostic outcome. Therefore it is recommended that all patients with cirrhosis or chronic viral hepatitis are screened every 6 months using ultrasound. In addition, HBV or HBV/HCV vaccination can serve as frontline prevention against hepatocellular carcinoma. 

Metastatic Disease

Key points

• Liver metastases are often asymptomatic in early stages, and usually originate from tumors in the lower digestive tract.
• Imaging techniques are used to visualize metastases. Biopsy of the tumor assists in determining its origin and grade, and allows for molecular analysis.
• In general, metastatic disease is incurable. The prognosis depends on the primary tumor type, tumor burden, and the patient’s condition.

General

Malignancies are becoming more common, and so is the incidence of liver metastases. Metastasis in the liver is a heterogeneous condition.

Symptoms

Small liver metastases do not cause any symptoms. When metastases are large or numerous, and a substantial part of the liver is damaged, patients may experience abdominal pain, weight loss and jaundice. When metastases compress the bile duct, jaundice can occur. The stage of the underlying malignancy and the extent of the disease contributes to the severity of symptoms.

Cause

Most liver metastases originate from tumors in the lower digestive tract. Detached tumor cells are carried by the bloodstream, via the portal vein, to the liver, where tumor cells adhere to liver cells. In malignancies outside the digestive tract, e.g., lung or breast, the detached tumor cells reach the liver via the hepatic artery.

Diagnosis

An ultrasound, CT scan or MRI can visualize metastases in the liver. A liver biopsy is necessary to determine the origin of the tumor. Also, the metastases can be graded and molecular analysis can be performed, which may be relevant for treatment.

Treatment

In general, metastatic disease is incurable. Treatment aims to control symptoms and improve or preserve the patient’s quality of life. Treatment options are chemotherapy, hormonal therapy, targeted therapy, immunotherapy or best-supportive care, depending on the primary tumor. Curative treatment, such as surgical resection, radiofrequency ablation or radiotherapy, can be applied in case the amount and size of metastases are small, metastases are all localized in one liver lobe, no metastases are outside the liver, the primary tumor is treatable, and the patient is in good condition. In practice, however, the risk of recurrence is very high.

Prognosis

The prognosis depends on the type of primary tumor and tumor burden and the patient’s condition.

Diseases of the Biliary Tract

Cholelithiasis

Key points

• Gallstones can be located in the gallbladder or bile ducts.
• Cholelithiasis is most prevalent in Northern European, Native American, and Hispanic populations; women are more often affected than men.
• Biliary colic is severe intermittent abdominal pain in the right upper quadrant caused by symptomatic gallstones that block bile ducts.
• In case of obstruction of the common bile duct, laboratory findings show elevated levels of AP, gamma-GT and bilirubin.
• The sensitivity of abdominal ultrasound in detecting gallstones is almost 100%.
• Treatment (only of obstructive stones) consists of cholecystectomy, or endoscopic retrograde cholangiopancreatography (ERCP) to unblock the common bile duct.

General 

Cholelithiasis, also known as gallstone disease, can be divided into gallstones in the gallbladder, i.e., cholecystolithiasis, and gallstones in the common bile duct, i.e., choledocholithiasis. The definition of a gallstone is based on its chemical composition: pure cholesterol, pure bilirubin, or mixed. Cholesterol stones are the most frequent type. 

Epidemiology

Cholelithiasis, both symptomatic and asymptomatic, affects 10 to 15% of the world’s population. The highest incidence of cholelithiasis is found in Northern European, Native American and Hispanic populations. In addition, women are more often affected than men.

Symptoms 

Cholelithiasis is usually asymptomatic if there is a small number of gallstones with a relatively small size located inside the gallbladder. Biliary colic might occur when a gallstone obstructs the cystic duct or common bile duct. Biliary colic is severe intermittent abdominal pain in the right upper quadrant and often occurs after a greasy meal as the demand for digestive juices increases. Biliary colic is usually accompanied by nausea, vomiting, and diarrhea. In addition, patients feel the urge to move. Sometimes the pain may radiate to the right shoulder or upper back, caused by diaphragm irritation. When the gallstone completely blocks the common bile duct, the stool will become clay-coloured, and even jaundice may occur.

Risk factors 

Advanced age, obesity, rapid weight loss, female gender, pregnancy, and use of oral contraceptives are associated with a higher risk of developing gallstones.

Cause 

The thickening of bile induces the formation of gallstones. Why bile thickens is only partially understood. It most likely has to do with an excess of cholesterol or bilirubin or a deficiency of bile salts. Female hormones, like estrogens, are believed to cause cholelithiasis by increasing the amount of cholesterol in the bile. Incomplete emptying of the gallbladder may also cause gallstones, since the residue will thicken.

Diagnosis

Asymptomatic cholelithiasis is usually detected incidentally on an abdominal ultrasound. Symptomatic patients often have no abnormal findings on physical examination. In case of prolonged blockage of the common bile duct by a gallstone, jaundice and signs of skin scratching can be found. Laboratory findings usually do not show elevations of the transaminases ALT and AST. However, in case of a blockage of the common bile duct, elevated levels of AP, gamma-GT and bilirubin can be present. When cholelithiasis leads to cholecystitis, cholangitis, or pancreatitis, an elevated CRP and sedimentation rate can be found. An abdominal ultrasound has a sensitivity of almost 100% in detecting gallstones. Its specificity is 18%. With a sensitivity of about 80%, a CT scan is less sensitive than an ultrasound.

Treatment

Asymptomatic cholelithiasis does not require treatment, as the chances of complications are low. However, treatment is indicated in symptomatic patients with severe recurrent symptoms and complications, such as cholecystitis, cholangitis or pancreatitis. A surgical laparoscopic cholecystectomy is the first choice of treatment. Sometimes an endoscopic retrograde cholangiopancreatography (ECRP) is needed first to unblock the common bile duct.

Prognosis

Patients with cholelithiasis have an average life expectancy. However, untreated complications of cholelithiasis, like cholecystitis, cholangitis or pancreatitis, can be life-threatening.

Cholecystitis

Key points

• Cholecystitis is an acute or chronic inflammation of the gallbladder, most commonly caused by an obstruction of the bile ducts by gallstones, i.e., calculous cholecystitis.
• Acalculous cholecystitis is cholecystitis caused by bacteria.
• A positive Murphy’s sign often suggests acute cholecystitis.
• Ultrasound is the diagnostic gold standard.
• Initial treatment consists of intravenous fluids, fasting, antibiotics, and analgesia.
• Cholecystectomy is recommended to prevent recurrent cholecystitis.

General 

Cholecystitis is an inflammation of the gallbladder caused by a mechanical obstruction, i.e., calculous cholecystitis, or a bacterial infection, i.e., acalculous cholecystitis. Cholecystitis can be acute or chronic.

Epidemiology

The incidence of cholecystitis varies worldwide. However, it is most frequently reported in Western countries. The incidence increases with older age. In addition, cholecystitis is seen more in women than in men.

Symptoms 

Acute cholecystitis presents sudden and persistent abdominal pain that may last for hours or days. It can be accompanied by anorexia, nausea and vomiting. The pain may radiate to the right shoulder or upper back, caused by diaphragm irritation. Patients prefer to lie as still as possible because of focal peritonitis. Fever is often present. Jaundice, caused by blockage of the common bile duct, is rarely seen.

Risk factors 

Cholelithiasis is the major risk factor for calculous cholecystitis. In addition, advanced age, obesity, rapid weight loss, female gender, pregnancy, and use of oral contraceptives are associated with a higher risk of developing gallstones. Common risk factors for acalculous cholecystitis are parenteral feeding or prolonged fasting and all conditions wherein patients are susceptible to infections, such as diabetes mellitus or AIDS. 

Cause

Calculous cholecystitis accounts for around 95% of all cases of cholecystitis. Calculous cholecystitis is caused by the mechanical obstruction of the cystic duct, usually due to gallstones but sometimes by sclerosis or compression from outside the cystic duct.

A bacterial or viral infection causes acalculous cholecystitis. In addition, when bile secretion is decreased, e.g., during prolonged fasting or parenteral feeding, bacteria from the intestine may migrate upstream towards the gallbladder.

Diagnosis

Physical examination usually reveals tenderness of the upper right quadrant of the abdomen. Murphy’s sign is positive if tenderness and guarding in the right hypochondrium are exacerbated by inspiration. The inflamed gallbladder then touches the examiner’s hand. A positive Murphy’s sign is found in the majority of patients. Sometimes the swollen gallbladder itself may be recognized on palpation, but deep palpation is often not feasible because of severe pain and peritoneal irritation. 

Laboratory findings usually show signs of inflammation, like an increased white blood cell count (WBC), CRP and sedimentation rate. However, usually, normal or non-elevated WBC values do not exclude the diagnosis, especially when short-term symptoms are present. In addition, serum bilirubin, AP, transaminases and amylase values may all be increased. Ultrasonography is the diagnostic gold standard. Ultrasound can identify gallstones, thickening of the gallbladder wall and pericholecystic fluid buildup. CT imaging can also be employed; however, it is much less sensitive than an ultrasound. 

Treatment

Nowadays, the initial treatment of calculous cholecystitis consists of intravenous fluids, fasting, antibiotics and analgesics. In most cases, after several days to a week, gallstones responsible for the cholecystitis fall back into the gallbladder, after which the inflammation subsides. After this initial treatment, laparoscopic cholecystectomy is recommended to prevent recurrent cholecystitis. Acute surgery is indicated in case of sepsis, gallbladder perforation or gangrenous cholecystitis. Percutaneous drainage of the inflamed bile is an option in inoperable patients.

Prognosis

Acalculous cholecystitis is associated with higher morbidity and mortality rates than calculous cholecystitis. However, after a cholecystectomy, it is possible to lead an average life, although some patients report symptoms of bloating and diarrhea.

Cholangitis

Key points

• Cholangitis refers to inflammation of the bile duct system caused by pathogens, i.e., infectious cholangitis, or an auto-immune disease.
• Patients with infectious cholangitis typically present with right upper quadrant abdominal pain, fever and jaundice, i.e., Charcot’s triad. 
• Treatment of infectious cholangitis consists of broad-spectrum antibiotics and decompression of the bile duct with endoscopic retrograde cholangiopancreatography (ERCP).
• Auto-immune causes of cholangitis include primary sclerosing cholangitis and primary biliary cholangitis.
• Primary sclerosing cholangitis is highly prevalent among young men, while primary biliary cholangitis primarily affects women.
• There is no established treatment for primary sclerosing cholangitis and primary biliary cholangitis. Ursodeoxycholic acid can slow disease progression and improve liver function.

Infectious cholangitis

General

When pathogens cause inflammation of the bile duct system, it is called infectious or ascending cholangitis. The common bile duct is the most affected site. Severity ranges from mild to life-threatening.

Epidemiology

In the United States, the incidence of acute cholangitis is 200.000 cases annually. The majority of patients with cholangitis are 50 to 60 years old. After an endoscopic retrograde cholangiopancreatography (ERCP), the risk of developing cholangitis is 0,5 to 1,7%. 

Symptoms

Acute infectious cholangitis is characterized by abdominal pain in the right upper quadrant, fever and chills. Jaundice may occur in case of obstruction of the common bile duct. Loss of appetite, nausea and vomiting are often present. The combination of abdominal pain in the right upper quadrant, fever and chills, and jaundice is called Charcot’s triad.

Risk factors

Gallstones are the major risk factor for infectious cholangitis. In addition, a stent in the bile ducts also increases the risk of bacterial cholangitis.

Cause

Infectious cholangitis is mostly a result of diminished bile excretion, e.g., caused by bile duct constriction, gallstones or a tumor. Due to this, bacteria from the intestine can migrate upstream into the common bile duct. ERCP is another cause of cholangitis since bacteria from the intestine may be dragged to the common bile duct by the scope. Bacteria that mainly cause infectious cholangitis are Escherichia coli, Klebsiella, Enterococcus, Enterobacter, Pseudomonas and anaerobes.  

Diagnosis

Laboratory findings usually show an elevated sedimentation rate, CRP and leukocytes. In addition, bilirubin, AP and gamma-GT may be elevated. Blood cultures should be taken before antibiotics are started, although bacteremia is only found in 5 to 6% of all patients with cholangitis. In addition, a culture of the bile should be taken when a therapeutic ERCP is performed. An ultrasound or CT scan can be performed to look for structural abnormalities like gallstones, strictures or tumors. 

Treatment

Decompression through ERCP with an optional sphincterotomy is the therapeutic gold standard in acute cholangitis. Unfortunately, percutaneous or surgical decompression has a higher morbidity and mortality rate. When an ERCP causes cholangitis, decompression is not necessary. Broad-spectrum antibiotics should be started as cholangitis is mainly caused by multiple bacteria. Once the blood or bile cultures show which bacteria are responsible for the cholangitis, antibiotic treatment can be adjusted.

Prognosis

Infectious cholangitis is a potentially lethal condition. Nevertheless, with early diagnosis and treatment, it is well-treatable. Factors associated with a poor outcome are older age, female gender, sepsis and underlying malignancy.

Primary Sclerosing Cholangitis

General 

Primary sclerosing cholangitis is a chronic and progressive disease characterized by inflammation, fibrosis, and stricture of intrahepatic and extrahepatic biliary ducts.

Epidemiology

The prevalence is highest among men between the ages of 20 to 40. In Caucasians, 21 per 100.000 males and 6 per 100.000 females are affected with primary sclerosing cholangitis.

Symptoms

Accidentally found abnormal liver enzymes (gamma-GT and AF) might be the first sign of primary sclerosing cholangitis. For that reason, around half of the patients are asymptomatic at diagnosis. At a later stage, complaints of right upper quadrant abdominal pain, pruritus, and fatigue are often reported. Weight loss and steatorrhea may also be evident. At the end stage of primary sclerosing cholangitis, symptoms of advanced liver cirrhosis, including jaundice, ascites, and confusion can be found.

Risk factors

Most patients with primary sclerosing cholangitis have underlying immune diseases, particularly inflammatory bowel disease, such as ulcerative colitis, and auto-immune hepatitis. In addition, several genetic factors are linked to primary sclerosing cholangitis.

Cause 

The etiology of primary sclerosing cholangitis is unknown, but it is thought to be an auto-immune disease. Autoantibodies are directed against bile duct cells, causing a chronic, sterile inflammation, followed by sclerosis and stricture of the intrahepatic and extrahepatic bile ducts. Strictures eventually obstruct the bile ducts, preventing bile from being excreted to the intestine. This process may cause steatorrhea and reduced absorption of nutrients. The accumulation of bile causes liver damage and, eventually, liver cirrhosis and liver failure.

Diagnosis

Biochemical tests usually demonstrate a cholestatic pattern, with an elevation of serum AP being a characteristic finding. Elevated serum bilirubin levels suggest a more advanced disease. In addition, autoantibodies such as p-ANCA can be detected. An ultrasound or CT scan may be performed to exclude biliary obstruction by gallstones or compression of bile ducts from structures outside the duct.

Multiple and focal areas being strictured and dilation of intrahepatic and extrahepatic bile ducts – like ‘beads-on-a-string’ – are characteristic of primary sclerosing cholangitis. This is best visualized with magnetic resonance cholangiopancreaticography (MRCP). A liver biopsy is rarely performed due to its invasiveness and risk of complications. However, during an ERCP, e.g., in case a stent is placed on improving bile secretion, it is possible to take an endoscopic biopsy. 

Figure 10. Endoscopic retrograde cholangiogram (ERCP) of a patient with primary sclerosing cholangitis (PSC). The ERCP shows the typical beads-on-a-string aspect. Within the intrahepatic bile ducts multiple strictures and sacculations are visible. Image courtesy of NTVG.

Treatment

There is no established treatment for primary sclerosing cholangitis. Ursodeoxycholic acid (UDCA) slows the disease process and partially improves liver function. However, existing sclerosis and liver damage are irreversible. In addition, it is essential to relieving symptoms such as itching and steatorrhea. Immunosuppressive and anti-inflammatory medications are unsuccessful. A liver transplant is the only possible cure for primary sclerosing cholangitis, but it carries a high risk of complications. Therefore this is only performed in fit patients with a life expectancy of less than one year or with severe symptoms interfering with the patient’s quality of life.

Prognosis 

Median survival from diagnosis without liver transplantation is 10 to 15 years. After liver transplantation, the 2-year survival is 80%, with a good quality of life.

Patients with primary sclerosing cholangitis should be screened annually for the development of cholangiocarcinoma and colon carcinoma (in patients with inflammatory bowel disease).

Primary Biliary Cholangitis

General 

Primary biliary cholangitis is an auto-immune disorder in which the intrahepatic bile ducts are chronically inflamed. As a result, constriction of the bile ducts occurs, leading to cholestasis and periportal inflammation. This subsequently leads to cirrhosis and portal hypertension. The course of primary biliary cholangitis varies significantly from patient to patient.

Epidemiology

Pooled global incidence and prevalence of primary biliary cholangitis are 1,76 and 14,60 per 100.000 individuals, respectively. Incidence and prevalence are lower in the Asia-Pacific region (0,84, 9,82 per 100.000 individuals) than that in North America (2,75, 21,81 per 100.000 individuals) and Europe (1,86, 14,59 per 100.000 individuals) (p < 0,05). It occurs most in women between 30-60 years old.

Symptoms 

In the initial stage, patients with primary biliary cholangitis can be asymptomatic. In more advanced stages, jaundice is evident and associated with symptoms of pruritus and fatigue. Hepatomegaly can be seen in asymptomatic patients and patients with more progressed-stage disease. Xanthelasma or xanthomas are often found in patients with primary biliary cholangitis. This results from hypercholesterolemia, caused by reduced excretion of fat and cholesterol via bile ducts. In addition, weight loss and steatorrhea may be present. 

Additional auto-immune conditions, like Hashimoto’s thyroiditis, Sjögren’s syndrome, rheumatoid arthritis, pernicious anemia, scleroderma, glomerulonephritis or renal tubular acidosis are associated with primary biliary cholangitis.

Cause 

The pathogenesis of primary biliary cholangitis is thought to result from an interaction between genetic predisposition and environmental triggers. Primary biliary cholangitis is an auto-immune disease in which autoantibodies are directed against intrahepatic bile duct cells, causing a chronic, sterile inflammation, followed by sclerosis and stricture of the intrahepatic bile ducts. Stricture eventually obstructs the bile ducts, preventing bile from being excreted to the intestine. This process may cause steatorrhea and reduced absorption of nutrients. In addition, the accumulation of bile causes liver damage, eventually leading to liver cirrhosis and liver failure.

Staging is classified by the extent of ductal destruction.

Stage 1–Demonstration of the destruction of interlobular bile ducts and granulomas

Stage 2–Exhibition of ductular proliferation.

Stage 3–Fibrosis is apparent

Stage 4–Liver cirrhosis 

Diagnosis

In asymptomatic patients, elevated AP levels may be the only sign of disease. At a later stage, bilirubin and gamma-GT levels are also elevated. Cholesterol is often elevated in patients with diminished bile excretion. Antimitochondrial antibodies (AMA) are found in 90 to 95% of patients with primary biliary cholangitis. 

An abdominal ultrasound, magnetic resonance cholangiopancreatogram (MRCP) or endoscopic retrograde cholangiopancreatogram (ERCP) can be made to rule out extrahepatic biliary obstruction. In addition, liver cirrhosis can be visualized with an ultrasound, CT scan or MRI. A liver biopsy is important to identify primary biliary cholangitis in AMA-negative patients. In AMA-positive patients with severely elevated liver enzymes (AST and ALT), a liver biopsy is performed to determine the disease stage and degree of liver damage.

Treatment

There is no established treatment for primary biliary cholangitis. Ursodeoxycholic acid seems to slow disease progression and partially improves liver function. However, existing sclerosis and liver damage are irreversible. In addition, it is important to relieve symptoms such as itching and steatorrhea. Patients should be advised not to drink alcohol.

Steroids and immunosuppressants are not yet part of standard treatment. In advanced stages of primary biliary cholangitis, liver transplantation can be considered, although this is a major intervention with a high risk of complications.

Prognosis 

Primary biliary cholangitis is a slowly progressive disease. On average, it progresses to terminal stages in 15 to 20 years, but the course of the disease varies significantly from patient to patient. Once liver cirrhosis has developed, the prognosis is poor.

Malignant Tumors of the Biliary Tract

Key points

• Malignancy of the biliary system is rare and refers to cholangiocarcinoma and gallbladder carcinoma.
• Cholangiocarcinoma affects men more often than women; gallbladder carcinoma is more often seen in women.
• Cholangiocarcinoma usually presents with painless obstructive jaundice.
• Gallbladder carcinoma usually only becomes symptomatic in the advanced stage.
• Cancer antigen 19.9 (CA19.9), is a marker for biliopancreatic tumors.
• Surgical resection is the only curative treatment option for cholangiocarcinoma and gallbladder carcinoma. 
• The prognosis of cholangiocarcinoma and gallbladder carcinoma remains poor even after resection.

Cholangiocarcinoma

General 

Cholangiocarcinoma is an adenocarcinoma that arises from the epithelial cells of the bile ducts. Based on the localisation, cholangiocarcinoma can be divided into intrahepatic and extrahepatic. Extrahepatic cholangiocarcinoma includes a carcinoma in the hepatic duct, i.e., hilar cholangiocarcinoma, or in the common bile duct, i.e., distal cholangiocarcinoma. Hilar cholangiocarcinoma was previously called Klatskin tumor.

Epidemiology

Cholangiocarcinoma is a rare cancer type. The incidence is approximately 1 to 2 per 100.000 individuals in Europe and North America. Cholangiocarcinoma has been reported across all age groups, and men are more often affected than women.

Symptoms 

Patients with cholangiocarcinoma usually present with painless obstructive jaundice. In addition, abdominal pain, weight loss, loss of appetite, fever and night sweating can be present. Abdominal pain is constantly present and not colic, unlike abdominal pain associated with cholelithiasis. Jaundice can be accompanied by pruritus.

Risk factors 

Most cases of cholangiocarcinoma are without apparent cause. However, the risk of cholangiocarcinoma is increased by the following conditions: choledochal cysts, primary sclerosing cholangitis, HVB and HVC, liver cirrhosis and parasitic infections like Fasciola hepatica. 

Diagnosis

Incidentally, cholangiocarcinoma can be diagnosed early through physical examination or imaging. However, in later stages, painless obstructive jaundice emerges. Laboratory findings show elevated bilirubin, AP and gamma-GT levels in case of obstructive jaundice. Serum IgG4 may be measured to exclude IgG4-related cholangiopathy. The cancer antigen 19.9 (CA19.9) is an effective marker in diagnosing cholangiocarcinoma, with a sensitivity of 77%.

Obstruction and dilation of bile ducts can be visualized by an ultrasound, CT scan or MRI. CT or MRI scans may be used to assess tumor size, the presence of enlarged lymph nodes – suggestive of lymph node metastasis –, vascular involvement and ingrowth in surrounding organs. An endoscopic retrograde cholangiopancreatography (ERCP) can be performed to obtain cytologic brushings. In obstructive jaundice, a stent can be placed during the ERCP procedure. Another way to obtain materials for pathology is by an ultrasound-guided histological biopsy or fine needle aspiration.

Treatment

Treatment depends on the stage of the disease. Surgical resection is the only chance to cure small tumors without lymph node metastasis.

Liver transplantation may be the only curative option for a selection of patients with intrahepatic cholangiocarcinoma. Chemotherapy is indicated for patients with unresectable or metastatic cholangiocarcinoma who are in good clinical condition. This palliative chemotherapy aims to reduce symptoms and hopefully extend the lifespan. 

Prognosis 

The prognosis is generally poor. The survival rate of patients with cholangiocarcinoma mainly depends on the disease stage and the associated resectability. Even after surgical resection, the 5-year survival rate is only 30%. Patients with inoperable or unresectable tumors have a median survival of 15 months. The prognosis is even worse in patients with cholangiocarcinoma with underlying primary sclerosing cholangitis.

Gallbladder Carcinoma

General

Gallbladder carcinoma is an aggressive type of cancer. Almost all gallbladder carcinomas are adenocarcinomas. 

Epidemiology

Gallbladder cancer is rare. The incidence is approximately 1 to 2 per 100.000 individuals. A higher incidence of gallbladder cancer is found in South America, Pakistan, Japan and India. In addition, gallbladder cancer is more common in women than in men.

Symptoms

Gallbladder carcinoma only becomes symptomatic in the advanced stage. The most common symptoms are abdominal pain, weight loss, jaundice, loss of appetite, fever, and nausea. Jaundice can be accompanied by dark urine and discolored stool.

Risk factors

The most common risk factor for gallbladder carcinoma is cholelithiasis. Up to 80% of all individuals with gallbladder carcinoma have gallstones. In addition, obesity and female gender are common risk factors. Polyps in the gallbladder can become malignant. The larger the polyp, the higher the risk. Approximately 3 to 8% of all polyps are malignant; polyps larger than 1 centimeter are malignant in 35 to 80% of the cases.

Diagnosis

Gallbladder carcinoma can be found accidentally, e.g., during a cholecystectomy because of symptomatic cholelithiasis. In these cases, the diagnosis is made by the pathologist. In more advanced stages, the diagnosis can be made based on symptoms, physical examination, laboratory examination, radiology and pathologic examination. On physical examination, jaundice can be seen. The abdomen may be tender on palpation and a palpable mass in the right upper quadrant can be found.

Laboratory findings show elevated bilirubin, AP and gamma-GT levels. The cancer antigen 19.9 (CA19.9), a marker of biliopancreatic tumors, has a sensitivity of 60 to 65% to detect gallbladder carcinomas. An ultrasound, CT scan or MRI can visualize the gallbladder and the tumor. In addition, CT or MRI scans may be used to assess tumor size, enlarged lymph nodes – suggestive of lymph node metastasis – and ingrowth in surrounding organs.

A biopsy of the gallbladder mass is only taken if there is doubt about the diagnosis. A cholecystectomy is performed in case of high suspicion of malignancy in small tumors without signs of metastasis since a biopsy risks the spreading of tumor cells. A biopsy of a metastatic site is taken in case of suspected metastasis.

Treatment

In small gallbladder carcinoma, limited to the gallbladder, a cholecystectomy is the only surgical option to cure this disease. Chemotherapy is indicated for patients with unresectable or metastatic cholangiocarcinoma, who are in a good clinical condition. The aim of this palliative chemotherapy is to reduce symptoms and hopefully extend the lifespan. In case of obstructive jaundice, percutaneous transhepatic drainage can be performed.

Prognosis

The prognosis of gallbladder carcinoma is poor. The overall 5-year survival of gallbladder carcinoma is 5 to 10%. The overall median survival after diagnosis is 3 to 6 months. A cholecystectomy can cure early-stage gallbladder carcinoma, but the chance of recurrence is still high. Individuals with gallbladder polyps should be closely monitored; how closely depends on the number, size and interim growth of the polyps. 

Diseases of the Exocrine Pancreas

Pancreatitis

Key points

• Pancreatitis is either acute or chronic, ranging from a duration of days to weeks to months. Chronic pancreatitis is recurrent.
• Major risk factors include smoking and alcohol use. In acute pancreatitis, obesity and the associated risk of gallstones are risk factors.
• Patients with pancreatitis have severe abdominal pain radiating to the back or shoulders. 
• In acute pancreatitis, amylase and lipase are significantly elevated. However, these markers are normal to slightly elevated in chronic pancreatitis.
• Acute pancreatitis is treated with fluid resuscitation as patients are often hypovolemic. Analgesia and treating underlying causes are also crucial.
• Chronic pancreatitis is treated symptomatically. The cause of chronic pancreatitis should be addressed to prevent further damage.

Acute Pancreatitis 

General 

Short-term inflammation of the pancreas lasting for several days to a few weeks is called acute pancreatitis. Acute pancreatitis can be classified as either edematous or necrotising pancreatitis. Necrotising pancreatitis is the most severe type and occurs in 20% of patients. 

Epidemiology

The incidence of acute pancreatitis ranges from 10 to 40 per 100.000 individuals. Due to the high prevalence of obesity and alcohol consumption, the incidence of acute pancreatitis is rising, particularly in Western countries. Up to the age of 60 years, acute pancreatitis is more common in men. In older people, acute pancreatitis is more often found in women.

Symptoms 

Acute and severe abdominal pain radiating to the back or shoulders is the most common symptom of acute pancreatitis. Patients tend to bend forward with their knees raised, decreasing the stretch of the pancreas and relieving the pain. In addition, decreased appetite, nausea and vomiting are often present. Fever occurs in about 60% of all patients with acute pancreatitis. Tachypnea is sometimes found as an expression of acute respiratory distress syndrome, pleural fluids or metabolic acidosis.

Jaundice can be found when the common bile duct is blocked due to gallstones or swelling of the head of the pancreas. In severe cases, hypovolemic shock and multi-organ failure can occur.

Risk factors 

Obesity and its associated risk of gallstones, smoking and alcohol abuse are the major risk factors for developing acute pancreatitis.

Cause 

Acute pancreatitis is usually caused by gallstones (40%) or excessive alcohol consumption (30%). Other causes are trauma, hypercalcaemia, hypertriglyceridemia, toxins or medications, viral infections (e.g., mumps) or cystic fibrosis. After an endoscopic retrograde cholangiopancreatography (ERCP), the chance of developing acute pancreatitis is 3 to 10%. 

Diagnosis

On physical examination, epigastric pain, tachypnea, tachycardia, hypotension and fever may be present during acute pancreatitis. In addition, Jaundice can sometimes be found. Amylase and lipase levels are elevated over 3 times as high as the upper limit of normal. Usually, sedimentation rate, CRP and leukocytes are also elevated. In case of obstruction of the common bile duct, elevated levels of bilirubin, gamma-GT en AP are found. In severe cases, diminished eGFR, electrolyte disturbances and metabolic acidosis can be present. When the cause of acute pancreatitis is unclear, serum triglycerides and calcium should be measured. 

An abdominal ultrasound can show an enlarged and edematous pancreas. Also, peripancreatic fluid and a dilated common bile duct can be found. In severe pancreatitis, it is advised to perform an abdominal CT scan after 72 to 96 hours to look for (secondary infected) necrosis.

Treatment

There is no medication to stop acute pancreatitis; the inflammation should recover independently. In acute pancreatitis, an attempt should be made to remove the underlying cause. In addition, an ERCP should be performed in case of obstructing gallstones. Intake of alcohol, toxins or medication should be stopped in case of toxic pancreatitis.

Most patients are hypovolemic. Therefore, adequate early fluid resuscitation is crucial, regardless of the cause. In addition, adequate pain relief, not infrequently with morphine, is necessary. There is no scientific agreement on whether a patient with acute pancreatitis should be fasting. 

In case of severe necrotizing pancreatitis, broad-spectrum antibiotics should be started. Sometimes surgical debridement is necessary to excise all dead and devitalized pancreatic and peripancreatic tissue. 

Prognosis 

About 80 to 90% of patients with acute pancreatitis recover without residual symptoms. However, in patients with severe acute pancreatitis with necrosis, secondary infections or multi-organ failure, the mortality rate is up to 50%.

Chronic Pancreatitis

General 

Long-term or recurring inflammation of the pancreas is called chronic pancreatitis. Eventually, due to this chronic inflammation, permanent damage to the pancreas will occur. Necrotic cells are replaced by fibrotic tissue, which could lead to narrowing of the pancreatic duct. The most common complications of chronic pancreatitis are (pseudo)cysts, exocrine pancreatic insufficiency and diabetes mellitus.

Epidemiology

In Western countries, the incidence of chronic pancreatitis ranges from 5 to 12 per 100.000 individuals. Chronic pancreatitis often affects patients aged 30 to 40 and is more common in men than women.

Symptoms

In chronic pancreatitis, periods with severe symptoms are alternated by periods with fewer or no symptoms. Abdominal pain radiating to the back or shoulders is the most common symptom. In addition, digestive problems, such as steatorrhoea, nausea and weight loss, are often present. Diabetes mellitus can occur when a substantial part of the pancreas is damaged. Unlike acute pancreatitis, fever is not a common symptom in chronic pancreatitis. Jaundice is found when fibrosis causes narrowing of the common bile duct or when a pancreatic cyst compresses the common bile duct.

Risk factors 

Alcohol abuse and smoking are risk factors for developing chronic pancreatitis. In idiopathic chronic pancreatitis, several genetic mutations are found.

Cause 

In 40 to 70% of all cases, chronic pancreatitis is caused by chronic alcohol abuse. Other causes are gallstones, hypercalcaemia, hypertriglyceridemia and toxins or medications. Recurrent acute pancreatitis, whatever the cause, may eventually lead to chronic pancreatitis. About 10-30% of chronic pancreatitis is idiopathic. In children, the most common cause of chronic pancreatitis is cystic fibrosis.

Diagnosis

Abdominal examination shows no typical signs of chronic pancreatitis. During acute exacerbations, epigastric tenderness can be found. In advanced cases of chronic pancreatitis, palpation may reveal an abdominal mass from a pseudocyst. Cachexia is found in the majority of patients with chronic pancreatitis. Serum amylase and lipase are usually within the normal range but may be slightly elevated. In case of obstruction of the common bile duct, elevated bilirubin, gamma-GT en AP levels can be found. In case of idiopathic chronic pancreatitis, genetic testing should be performed. The degree of inflammation and the presence of (pseudo)cysts can be visualized by an abdominal CT scan or magnetic resonance cholangiopancreatography (MRCP).

Treatment

There is no cure for chronic pancreatitis. Removing the underlying cause, mostly alcohol abuse, is essential in preventing further damage to the pancreas. Damage done to the pancreas will be irreversible. Analgesics should be prescribed to relieve abdominal pain. In addition, oral administration of pancreatic enzymes is necessary in case of exocrine pancreatic insufficiency. Symptomatic (pseudo)cysts can be treated by endoscopic or percutaneous drainage, laparoscopic surgery or open surgery. If chronic pancreatitis leads to diabetes mellitus, this should also be treated.

Prognosis 

The prognosis of patients with chronic pancreatitis is determined according to age at diagnosis, smoking, continued use of alcohol, and the presence of liver cirrhosis. The overall 10-year survival rate is 70%. The overall 20-year survival is 45%.

Exocrine Pancreatic Insufficiency

Key points

• Exocrine pancreatic insufficiency refers to insufficient or absent production of pancreatic enzymes. These enzymes help digest sugars, proteins and fats.
• Most often, exocrine pancreatic insufficiency is caused by chronic pancreatitis.
• The most common symptom is an altered stool pattern. Patients might experience steatorrhoea, osmotic diarrhea or undigested food residues in stool.
• Stool examination shows lowered levels of elastase and increased levels of fat.
• Treatment aims to prevent further damage and supplement pancreatic enzymes, especially when fatty foods are consumed.

General 

Pancreatic enzymes play an active role in the digestion of sugars, proteins, and fats. Exocrine pancreatic insufficiency refers to no or insufficient production of digestive enzymes by the pancreas and subsequent digestive problems.

Epidemiology

The prevalence of exocrine pancreatic insufficiency in Western countries is 8 per 100.000 males and 2 per 100.000 women. About 80% of all patients with chronic pancreatitis develop exocrine pancreatic insufficiency.

Symptoms 

An altered stool pattern is the most common symptom in exocrine pancreatic insufficiency, since the digestion of food is disturbed. Insufficient fat digestion leads to steatorrhoea and greasy, smelly and floating stool that is difficult to flush. Insufficient sugar digestion leads to osmotic diarrhea. In addition, undigested food residues can be found in stool. Other symptoms are abdominal pain, weight loss and fatigue.

Cause 

Exocrine pancreatic insufficiency is caused by substantial damage to the pancreas. Chronic pancreatitis is the most common cause. Pancreatic carcinoma, cystic fibrosis and the Shwachman-Diamond syndrome, which is a rare hereditary disorder, are other causes. How the pancreas is damaged differs according to the underlying cause: inflammation, fibrosis, or displacement by malignant cells. However, all types of damage result in exocrine pancreatic insufficiency.

Diagnosis

There is no specific blood test to diagnose exocrine pancreatic insufficiency. However, laboratory findings may show a deficiency of fat-soluble vitamins (A, D, E and K), magnesium, calcium and lipoprotein A and C. Stool examination reveals diminished elastase and increased fat. A secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) can detect subtle ductal changes and allow for a semiquantitative assessment of pancreatic exocrine function.

Treatment

Oral administration of pancreatic enzymes is the major component of treatment. These enzymes should be taken with every meal or snack that contains fat, especially meat, dairy, bread and desserts. Since hypocalcemia and decreased vitamin D levels are often present in patients with exocrine pancreatic insufficiency, screening for and treatment of osteoporosis is advised. Pancreatic damage that causes exocrine pancreatic insufficiency is usually permanent. If possible, further damage to the pancreas must be prevented. In alcoholic pancreatitis, for example, alcohol consumption should be ceased immediately.

Prognosis 

The prognosis of patients with exocrine pancreatic insufficiency depends on the underlying cause. Exocrine pancreatic insufficiency is associated with an increased mortality risk in patients with chronic pancreatitis, as chronic pancreatitis is associated with pancreatic cancer, infections, and cardiovascular events.

Malignant Tumors

Pancreatic Adenocarcinoma

Key points

• Adenocarcinoma is the most common type of pancreatic cancer. 
• Major risk factors include smoking and chronic pancreatitis.
• Symptoms usually arise at an advanced stage once the malignancy compresses surrounding structures or disturbs the function of the pancreas.
• Routine laboratory findings are usually normal. Cancer antigen 19.9, or CA19.9, has an 80% sensitivity for detecting pancreatic carcinoma. 
• A pancreatic biopsy is essential for histologically confirming the malignancy and type of tumor.
• In case of early detection of adenocarcinoma, curative treatment is possible and consists of surgery and adjuvant chemotherapy.
• Even after surgery, the 5-year survival is only 10 to 20%.

General 

Pancreatic cancer is an aggressive type of cancer. Adenocarcinoma is the most common histological type of pancreatic cancer. Unfortunately, because of the lack of symptoms at an early stage, the diagnosis is often made at an advanced stage, leading to a poor prognosis. In 2 out of 3 cases, the tumor is located in the head of the pancreas.

Epidemiology

Pancreatic (adeno)carcinoma is a rare type of cancer. The incidence is 10 to 14 per 100.000 individuals per year. Men are affected twice as much as women. Most patients are aged over 60.

Symptoms 

At an early stage, symptoms are absent. Only when there is compression of the bile duct or the coeliac plexus, directional symptoms do occur. In case of bile duct compression, jaundice is the major symptom. In case of coeliac plexus compression, abdominal pain or back pain is most prevalent. Other symptoms are steatorrhoea, loss of appetite, weight loss, fatigue and night sweats. Since the endocrine function of the pancreas may be affected, diabetes may occur, leading to symptoms associated with hyperglycemia. Patients with pancreatic carcinoma have an increased blood clotting tendency; it is not uncommon that presenting symptoms are due to a thromboembolic event.

Risk factors 

Smoking and chronic pancreatitis are major risk factors for developing pancreatic cancer. 

Diagnosis

A pancreatic tumor is rarely found unintentionally when abdominal imaging is performed for another reason. In most cases, however, the diagnosis is made at an advanced stage. On physical examination, jaundice may be seen in case of bile duct compression. A mass may be palpable in the epigastric region in case of a large tumor.

Laboratory findings show elevated bilirubin, AP and gamma-GT levels in case of bile duct obstruction. Cancer antigen 19.9, or CA19.9, is a marker of biliopancreatic tumors, with a sensitivity of 80% for pancreatic carcinoma. In addition, elevated glucose levels may be found.

An abdomen ultrasound or CT scan is performed to detect the pancreatic tumor. A CT scan or MRI best visualizes ingrowth in surrounding tissues. Since pancreatic tumors metastasize early, a whole-body CT scan or PET-CT scan is recommended for staging the disease. A pancreatic tumor biopsy is essential for histologically confirming the malignancy and type of tumor. A biopsy can be done through a radiology-assisted percutaneous puncture, endoscopic ultrasound or brushing during endoscopic retrograde cholangiopancreatography (ERCP).

Treatment

If the disease is detected at an early stage, curative treatment is possible. The most common surgical technique to remove a tumor in the head of the pancreas is the pancreaticoduodenectomy, i.e., the Whipple procedure. Adjuvant chemotherapy is advised if the patient is in good condition, as recurrence of pancreatic cancer develops in approximately 75% of the patients within 2 years. 

When there are no curative treatment options, e.g., when a tumor is unresectable or in case of metastatic disease, palliative chemotherapy can be considered. Palliative chemotherapy aims to reduce symptoms and extend the lifespan. 

Radiotherapy, radiofrequency ablation and immunotherapy show promising results in the context of a clinical trial, but are no first-choice treatments. 

In case of obstructive jaundice, an ERCP with stenting can be performed to relieve symptoms. Since steatorrhea is a common complaint in patients with pancreatic cancer, pancreatic enzymes should be administered.

Prognosis 

The prognosis of pancreatic cancer is poor. The overall 5-year survival after surgery ranges between 10 and 25%. The median survival of metastatic pancreatic carcinoma without palliative chemotherapy is 6 months.

Neuroendocrine Carcinoma 

Key points

• Pancreatic neuroendocrine malignancies are rare tumors arising from the pancreas’ hormone-producing cells.
• Whether a pancreatic neuroendocrine malignancy is called a pancreatic neuroendocrine tumor (pNET) or neuroendocrine carcinoma (pNEC) depends on the aggressiveness and the mitotic index.
• Functional pancreatic neuroendocrine malignancies are usually detected early as they overproduce hormones that cause symptoms.
• Non-functional pancreatic neuroendocrine malignancies do not produce hormones and are usually detected at a later stage.
• A biopsy is needed to determine the type and grade of the pancreatic tumor.
• The prognosis depends on the aggressiveness, grading and stage of the tumor.

General

Pancreatic neuroendocrine malignancies are a group of cancers arising from hormone-producing cells of the pancreas. Whether a pancreatic neuroendocrine malignancy is called a pancreatic neuroendocrine tumor (pNET) or neuroendocrine carcinoma (pNEC) depends on the aggressiveness and the mitotic index. Pancreatic neuroendocrine malignancies are either functional, i.e., they produce hormones, or non-functional, i.e., they produce no hormones. Hormones that are most often produced are gastrin, insulin, glucagon, somatostatin or vasoactive intestinal peptide (VIP).

Epidemiology

Neuroendocrine malignancies of the pancreas are rare, with an incidence lower than 1 per 100.000 individuals annually. Caucasian males are mostly affected. Of all pancreatic malignancies, only 5 to 7% are pNET or pNEC. The mean age of patients with neuroendocrine pancreatic malignancies is 55 to 60. Patients with a functional malignancy are often slightly younger than patients with a non-functional malignancy. 

Symptoms 

Patients with functional pNET and pNEC usually present with symptoms at an early stage. Symptoms mainly depend on the type of hormone produced, e.g., reflux and heartburn in gastrinoma, sweating and tremor (hypoglycemia) in insulinoma, thirst and polyuria (hyperglycemia) in glucagonoma, steatorrhoea in somatostatinoma, and watery diarrhea and electrolyte disturbance in VIPoma. On the other hand, symptoms related to non-functional pNET and pNEC usually occur at a later stage. These symptoms include fatigue, nausea, loss of appetite, weight loss, and jaundice in case of compression of the common bile duct.

Risk factors 

In 90% of all cases, pNET and pNEC are not inherited and occur sporadically. In Multiple Endocrine Neoplasia Type-1 (MEN1), which is an autosomal dominantly inherited syndrome, about 30 to 75% of people will develop pancreatic neuroendocrine tumors.

Diagnosis

As mentioned under ‘symptoms’, functional neuroendocrine malignancies of the pancreas are often diagnosed earlier than non-functional neuroendocrine malignancies. Laboratory findings may show elevated bilirubin, AP and gamma-GT levels in case of common bile duct obstruction. In addition, Chromogranin A, a secreted protein, may be increased in more than 60% of patients with both functional and non-functional pNET/pNEC.

The table below gives an overview of the different types of functional pNET and pNEC, their symptoms and which tests should be performed.

Tumor	Clinical features
	Hormone	Symptoms	Markers/tests
Gastrinoma	Gastrin	Recurrent acid related disease: ulcers or reflux.	Serum gastrin ↑ Gastric pH Secretin suppression test
Insulinoma	Insulin	Hypoglycemia symptoms	Glucose ↓ Insulin ↑ Pro-insulin ↑ beta-hydroxybutyric acid ↓ C-peptide suppression test
Glucagonoma	Glucagon	Necrolytic migratory erythema Diabetes mellitus Weight loss	Glucagon ↑ Glucose ↑
Somatostatinoma	Somatostatin	Mild diabetes mellitus Steatorrhoea Cholelithiasis	Somatostatin ↑
VIPoma	VIP	Diarrhea Dehydration	VIP fasting level ↑ Potassium ↓

Table 4. An overview of the different types of functional pNET and pNEC.

Neuroendocrine pancreatic malignancies can be visualized by an abdominal ultrasound, CT scan or MRI. An FDG-PET scan can detect metastases, although not all neuroendocrine malignancies are FDG-positive. A somatostatinoma can be visualized with a Ga-68-DOTATATE PET scan. A histological biopsy – either a radiology-assisted percutaneous puncture or an endoscopic ultrasound puncture –  is needed to determine the type and grade of the tumor.

Treatment

If a neuroendocrine malignancy is detected at an early stage, curative treatment is possible. The most common surgical procedure to remove a tumor in the head of the pancreas is a pancreaticoduodenectomy, i.e., the Whipple procedure. Unresectable or metastasized pancreatic neuroendocrine tumors can be treated with somatostatin analogues, interferon-alpha or vascular endothelial growth factor (VEGF) inhibitors. Unresectable or metastasized pancreatic neuroendocrine carcinoma can be treated with palliative chemotherapy. If neuroendocrine tumors are unresectable or metastasized, treatment aims to reduce symptoms and extend the lifespan. 

Prognosis 

The prognosis of a pancreatic neuroendocrine malignancy depends on the aggressiveness, tumor grade and stage. Low-grade neuroendocrine tumors grow slowly and are often curable or, in case of metastatic disease, can be controlled for several years. High-grade neuroendocrine carcinomas metastasize at an early stage and although the first response to chemotherapy is good, relapse usually occurs within a few weeks to months.