Acute viral hepatitis is a systemic illness that mainly affects the liver. Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis E virus (HEV) are the viruses that cause almost all instances of acute viral hepatitis. Hepatitis can be present with little or no symptoms, although it frequently results in jaundice, anorexia, and malaise. Hepatitis infection is divided into two types: acute and chronic. Acute hepatitis remains for less than six months, whereas chronic hepatitis stays for an extended period. 

The causes can also be triggered by chemical substances, the 'Drug Induced Liver Injury'.

Acute infectious hepatitis is mainly caused by specific hepatitis viruses: hepatitis A, B, C and E. Associated with the hepatitis B virus (HBV), infection with the delta virus can occur. This virus needs the HBV to replicate and is mainly found in Türkiye  and the Balkan states.

In addition, acute infectious hepatitis can also be triggered by non-specific liver viruses, such as Epstein-Barr virus (causative agent of mononucleosis, which is associated with sore throat and splenomegaly) and cytomegalovirus (CMV), which can flare up mainly after organ transplants.

In addition, there are exceptionally microbial causes, such as Q fever (histologically characterized by fibrin ring granulomas), syphilis (via homophilic contacts) and spirochetosis ictero-hemorragica (transmitted by rats via contaminated water).

The clinical signs are the development of jaundice (on average in one in three), pronounced fatigue and possibly skin rash, joint swelling and gastrointestinal discomfort (mainly due to the hepatitis A virus). The recovery phase lasts several weeks, but may be associated with severe post-viral asthenia. Laboratory tests show a very strong increase in transaminase and, in severe forms, an increase in bilirubin and international normalized ratio (INR). In addition to specific antiviral therapy for some conditions, relative bed rest is recommended and work can be resumed when transaminases are normal.

Since acute infectious hepatitis can make patients more susceptible to the hepatotoxicity of medications, all non-essential medications should be discontinued, including estrogens, which increase the risk of cholestatic hepatitis after hepatitis A. There is no place for the use of corticosteroids.

The infection is fecal-oral. The incubation period is about 2 to 6 weeks. An infected person can be contagious from 2 to 5 weeks before the onset of jaundice, until the disappearance of clinical symptoms. Acute hepatitis A can occur in small epidemics.

The disease never becomes chronic and its evolution depends on the age at which the infection occurs. In children, the disease is usually subclinical, while in people over 45 years of age, there is a mortality of more than 2% (partly due to acute liver failure).

Intake of estrogens (via oral contraception) may lead to cholestasis after the first phase of severe hepatitis. In a minority of adults the disease may be biphasic. Rarely acute hepatitis A provokes chronic autoimmune hepatitis. The diagnosis is made by an increase in bilirubin, a marked increase in transaminases and when the anti-hepatitis A IgM (class M immunoglobulin) becomes positive. Hepatitis A can be prevented by a vaccine. This is recommended when travelling to endemic areas. The first administration should preferably be received fourteen days before departure.

Acute hepatitis A does not require antiviral therapy. Urgent vaccination of the partner would make the course of the disease milder if there had been an infection.

Although this illness has decreased in developed countries due to extensive immunization, numerous developing and under-developed countries are struggling with this virus. HAV infection can be spread by oral-fecal contact, and there are frequent epidemics through nutrition. Improvements in socioeconomic and sanitary circumstances have caused a shift in the disease's prevalence worldwide. Younger children are usually asymptomatic, but as they become older, the infection symptoms begin to appear. Symptoms range from slight inflammation and jaundice to acute liver failure in older individuals. While an acute infection may be self-limiting, unrecognized persistent infections, and the misapplication of therapeutic methods based on clinical guidelines are linked to a higher incidence of cirrhosis, hepatocellular carcinoma, and mortality. Fortunately, most patients recover within two months of infection, though 10–15% of patients will relapse within the first six months. A virus seldom leads to persistent infection or liver damage. The mainstay of therapy is based on supportive care. All children from 12–23 months, as well as some susceptible populations, should receive routine vaccinations, according to the Centers for Disease Control and Prevention and the American Academy of Pediatrics. Laboratory diagnosis of HAV is based on antigen detection, checking liver enzyme levels, and antibody screening. Furthermore, polymerase chain reaction (PCR) technology has identified HAV in suspected nutrition sources; therefore, this technique is used for preventative measures and food-related laws. 

HAV infection is highly contagious, and it is a leading cause of acute hepatitis. In people with chronic liver disorders, acute HAV infection can induce liver failure. HAV seroprevalence is also relatively low in high-income provinces. Socioeconomic factors, access to clean water, and proper sanitation are all strongly linked to epidemiology. HAV usually causes short-term, self-limiting illnesses that go away without any long-term effects in 4–7 weeks. Dissimilar to HBV and HCV, HAV seems not to cause persistent liver damage. However, particularly in the elderly, severe fulminant hepatitis with possibly fatal liver failure may ensue. The associated risk factors that cause case-to-case variation in the degree of liver disease and recurrence remain unclear. Furthermore, contact with the feces of infected patients with HAV can result in the transmission of the virus, implying that the virus can be spread via oral-fecal transmission. It is widespread, although it is more common in less-developed areas with inadequate sanitary and hygienic conditions. Transfusion transmission of HAV is exceedingly rare due to the short persistence of viremia throughout acute HAV infection (approx. 10–50 days). However, donors should be reminded that if they are identified with blood-borne diseases after donating blood, they must inform the blood center. If a transfused individual shows hepatitis A symptoms with no record of traveling or oral-fecal disease, doctors should evaluate the potential of transfusion-transmitted hepatitis A. 

In collaboration with state and local health departments, CDC launched a large-scale, multidisciplinary response in 2017 to control the ongoing outbreaks associated with person-to-person transmission. To provide hepatitis A vaccination to disproportionately affected populations most affected by the outbreaks, health departments developed and implemented nontraditional vaccination and staffing strategies. These included holding satellite vaccination clinics (e.g., at correctional facilities, substance use treatment facilities, syringe services programs, and homeless shelters) and broadening the scope of health care professionals approved to administer vaccines. To overcome barriers to vaccination, including mistrust, stigma, and vaccine hesitancy, health departments partnered with organizations that have long-standing, trusted relationships with persons at risk for HAV infection. In September 2022, as a result of these intensive and innovative efforts, 24 states have officially declared their outbreaks over, and the remaining 13 states report decreased case counts from the peaks of their outbreaks.

The findings in this report are subject to at least five limitations. First, risk factor data were self-reported and subject to recall and social desirability biases. Second, hepatitis A surveillance in the United States is passive; thus, case counts might underestimate the actual number of cases. Third, a substantial proportion of data was missing; caution should be exercised when interpreting results with high rates of missing data. Fourth, ethnicity was not systematically ascertained and could not be included. Finally, states did not use an identical hepatitis A–related death case classification, which might have resulted in differential classification of deaths as being hepatitis A–related.

Hepatitis A epidemiology in the United States has shifted as a result of the ongoing outbreaks associated with person-to-person transmission. Cases occurred almost exclusively among adults, and HAV transmission was driven primarily by close contact among persons who use illicit drugs and persons experiencing homelessness. Improving services for these populations, including access to substance use treatment and sanitation, are important considerations in mitigating HAV transmission. Many adults at increased risk for HAV infection remain vulnerable to infection, despite long-standing vaccination recommendations. Given the high hospitalization rate during these outbreaks and the high level of susceptibility to HAV infection among adults in the United States, efforts are needed to improve awareness of and adherence to ACIP hepatitis A vaccination recommendations. Increased hepatitis A vaccination coverage, through implementation of nontraditional vaccination strategies to reach disproportionately affected populations, along with improved universal and catch-up childhood vaccination, will be necessary to respond to the current hepatitis A outbreaks and prevent similar outbreaks in the future. Lessons learned during these outbreaks have been reinforced by experiences during the COVID-19 pandemic and other vaccine-preventable disease outbreaks. Disproportionately affected populations often experience stigma, mistrust, and societal barriers that limit adequate access to the health care system. Continued improvements in vaccination infrastructure, immunization information systems, and education and outreach are critically needed to build vaccine confidence and improve vaccine delivery in nontraditional settings.

Risk areas for travellers

Over the last decades, a substantial decrease in incidence of hepatitis A infection has been observed worldwide due to better food and water hygiene, improved sanitation, increasing socio-economic standards and (in few countries) the implementation of hepatitis A vaccine in the childhood vaccination programmes. Therefore, many countries are evolving from high and intermediate endemicity towards intermediate and low endemicity respectively.

Regions with high endemicity are sub-Saharan Africa and parts of South Asia (Afghanistan, Bangladesh, Bhutan, India, Nepal, Pakistan). Hepatitis A is typically acquired during childhood, providing immunity for nearly all adults. Considering most children experience an asymptomatic disease course, outbreaks are rather exceptional.

Intermediate endemic areas are Latin America, North Africa, the Middle East and multiple countries in Asia. The infection is less frequently acquired during childhood, leaving more adults susceptible to hepatitis A. Hence, outbreaks are more common.

Western Europe, Canada, USA, Australia, New Zealand and some high income countries in Asia (Japan, South Korea, Brunei, Singapore) have a low to very low endemicity. The risk of getting infected with hepatitis A virus in these areas is thus low.

Infection occurs through blood contact, sexual contact and transmission from mother to child (vertical transmission). The incubation period is 8 to 24 weeks. The diagnosis is made by a very strong increase in transaminases, which may or may not be accompanied by an increase in bilirubin. The hepatitis B surface antigen becomes positive, as does the hepatitis B DNA. 

The course of the disease is determined by the age at which you come into contact with the virus. In newborns, the infection is usually subclinical, but leads to chronicity in 90% of babies. In children, the chance of chronicity is 20% and in the elderly less than 10%. Acute hepatitis B is a rare cause of acute liver failure (ALF).

Mother-to-child transmission is virtually universal. Transmission occurs during childbirth and therefore a caesarean section* is of no benefit. All children of a hepatitis B surface antigen-positive mother should be vaccinated and given immunoglobulins immediately after delivery. Mothers with very high viraemia (> 200,000 IU/ml) are best treated with a polymerase inhibitor in the third trimester of pregnancy.

Acute hepatitis B should not be treated with antiviral therapy unless after several weeks it appears that the serum hepatitis B DNA is still strongly positive. In that case, antiviral therapy can be considered.

Hepatitis C virus (HCV) chronically infects 58 million people worldwide, and chronic hepatitis C (CHC) is a major cause of serious liver diseases such as potentially fatal hepatic cirrhosis and hepatocellular carcinoma (HCC). HCV infection accounts for one in four cases of liver cancer (Bartenschlager et al, 2018).

Although the cure rate of CHC patients has significantly improved with the use of directly acting antiviral agents (DAAs), there is currently no prophylactic vaccine available. Additionally, cured patients may still be at risk for reinfection due to lack of protective immunity (Farci et al, 1992; Page et al, 2009). Moreover, the persistent risk of HCC development post‐treatment, emergence of drug resistance‐associated substitutions (RAS) and new subtypes, as well as limited access to DAA therapy in underdeveloped regions pose significant challenges to achieving the goal of eliminating viral hepatitis as a public health threat by 2030 (Bartenschlager et al, 2018; Shah et al, 2021). Therefore, HCV infection will continue to be a global public health concern.  

The mode of infection is mainly through contaminated blood, including needle stick injuries or intravenous/intranasal drug use. Hepatitis C is not a classic sexually transmitted disease (STD), but can be transmitted through rough anal contact. It can also be transmitted through vertical contamination, but this is generally low (< 5%).

Diagnosis is made by a marked increase in transaminases, possibly accompanied by an increase in bilirubin and hepatitis C RNA that becomes positive. Hepatitis C antibodies appear after 4 to 12 weeks. 75% of infections become chronic. There is no vaccine.

Antiviral therapy is started when the disease becomes chronic.

Pathogenesis|clinical picture

In most cases (80%), HCV infection becomes chronic, despite the presence of antibodies and HCV-specific T cells. After an incubation period of 2 months (range 2 to 26 weeks), infection with HCV leads to jaundice (icterus) in only 10% of cases. In half of the HCV carriers, ALT values ​​remain more or less elevated.

The physician encounters HIV mainly in the form of chronic hepatitis and cirrhosis (20% after 20 years). The chance of developing cirrhosis is higher in men, in HCV infection at an older age and if the HCV carrier uses alcohol. Modest alcohol use and diabetes mellitus also worsen the prognosis of hepatitis C initially. In addition to liver disease, HCV infection is associated with several other conditions. A significant proportion of patients with membranoproliferative glomerulonephritis type 1 and 'mixed cryoglobulinemia' are found to be HCV positive [Mixed cryoglobulinemia can evolve into a florid B-cell malignancy in up to 11% of cases].

Treatment HCV

The highly effective oral agents used in HCV (effective in 80-100% of treated patients) cannot all be used safely in the more advanced stages of fibrosis and cirrhosis. Liver biopsy in chronic HCV infection has the main role to grade fibrosis and inflammation and to establish a competing diagnosis (alcoholic liver disease or drug hepatitis). In addition, liver biopsy can be used to document progression of liver disease over time, which is not possible with serum transaminase determination. In addition to liver biopsy, ultrasound fibroscan and various blood tests can be used. The degree of fibrosis plays a role in determining the degree of urgency to proceed with treatment. From mild to moderate fibrosis, treatment is urgently needed. In severe fibrosis, liver transplantation should be considered.

Prevention

Passive or active immunization against hepatitis C is not available. The chance of infection with HCV after a needle stick injury with HCV-positive blood is 1-10%. Depending on the type of accident and the amount of infectious material transmitted.

Young people are usually infected by staying in endemic areas. Sporadic forms are increasingly appearing in adults. The infection is transmitted by zoonosis, including contact with infected pork. The virus can also be transmitted by blood transfusion.

The diagnosis is made by a marked increase in transaminases, which may be accompanied by an increase in bilirubin, the appearance of anti-hepatitis E virus IgM antibodies and a positive hepatitis E virus RNA. The most common genotype in the West is genotype 3.

Acute hepatitis E usually does not become chronic. The HEV RNA remains in the blood for 2 to 3 weeks. Only in patients under immunosuppression, for example after a transplant, can it become chronic.

An important complication is the development of serious neurological abnormalities, including Guillain-Barré syndrome. This is also called Hepatoneural syndrome.

There is no vaccine yet in the West. Acute hepatitis E does not need to be treated either. When hepatitis E becomes chronic, it can be cured by an antiviral drug. This is successful in 75% of cases.

Characteristics|epidemiology

Hepatitis delta virus (HDV) is not related to any other human or animal virus. HDV more or less parasitizes HBV, because it uses the envelope of HBV as an envelope. Infection with HDV is therefore only possible in the presence of infection with HBV.

Sporadic cases of HDV infection occur worldwide. The virus is found relatively often in intravenous drug users. HDV spreads mainly through blood-to-blood contact.

Hepatitis Delta virus life cycle HDV is the smallest human infecting virus and the sole member of the Deltavirus genus. HDV is characterized as a “satellite” or “defective” virus as it is dependent on HBV co-infection for viral assembly and persistence. HDV has an approximate 1.7 kb circular, single-stranded, negative-sense RNA genome that encodes for a single protein of two isoforms: The small and large delta antigens (S-HDAg and L-HDAg, respectively). Viral entry occurs similarly to HBV due to HDV’s co-opted use of the envelope HBsAg protein. Following viral entry, HDV uncoats in the cytoplasm and the ribonucleoprotein complex consisting of the HDV viral genome and HDAg complex is imported into the nucleus. Rolling-circle replication occurs in the nucleolus using the host RNA polymerase II to produce antigenomic positive sense HDV RNA that serves as a template for genomic HDV RNA synthesis and protein production. The antigenome can be edited by host protein adenosine deaminase acting on RNA 1 (ADAR1) to change adenine to inosine in the UAG stop-codon to produce the L-HDAg. The edited and non-edited antigenomes are then linearized by the HDV associated ribozyme, exported to the cytoplasm, and translated to HDV antigens. The non-edited transcript produces S-HDAg (24 kDa) and the transcript modified by ADAR1 produces the L-HDAg (27 kDa). Following extensive post-translational modifications, the viral antigens associate with the HDV RNA in the cytoplasm to form the ribonucleoprotein complex. The ribonucleoprotein is trafficked through the ER and Golgi apparatus where it co-opts the HBsAg envelope produced by HBV, and then buds out of the cell.

D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26(38): 5759-5783 [PMID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] 

This presents as abnormal liver tests (all types) after taking medication.

The provoking substances themselves are usually of little or no toxicity, but toxic metabolites may be formed. Rarely, there is idiosyncrasy (immunoallergy), which is characterized by eosinophilia, but usually the toxicity is dose-dependent. The amount and activity of some metabolizing enzymes in the liver are genetically determined. A person who has a genetic predisposition to rapid conversion to a toxic liver product is more likely to have toxic side effects. Elderly and patients with cirrhosis are at increased risk. For example, the maximum daily dose of paracetamol in cirrhotic patients is 2 g instead of 4 g. Certain medications can induce or inhibit the microsomal enzymes that detoxify the metabolites (see drug interactions when taking antiviral medication for hepatitis C).

In 70% of cases, toxicity is caused by one specific drug and in 20% of cases by a combination of different drugs. In 10% of cases, toxicity is provoked by dietary supplements or herbs.

The most frequent medications that cause hepatotoxicity are:

1) antibiotics (45%): such as amoxicillin-clavulanic acid, flucloxacillin and macrolides;

2) antiepileptics (15%): such as valproate and carbamazepine;

3) anti-inflammatory drugs: such as diclofenac and nimesulide.

DILI can result in several types of biochemical abnormalities. It can cause liver steatosis, including by mitochondrial toxicity, such as by taking steroids, tetracyclines, methotrexate and non-steroidal antiphlogistics (NSAID). It can give a picture of hepatitis, such as in the case of an overdose of paracetamol, antituberculostatics and antiepileptics. Finally, it can lead to cholestasis, such as by the intake of estrogens and amoxicillin-clavulanic acid.

Diagnosis is made by exclusion diagnosis. Accurate history and heteroanamnesis are crucial. In case of acute presentation, a toxicology screen of urine should be performed.

Almost 80% of DILI cases recover spontaneously. Very rarely, permanent damage to the small bile ducts (vanishing bile duct syndrome) may occur. DILI is a not infrequent cause of acute liver failure.

Small acetaminophen are efficiently processed in the liver to glucuronide or sulphate derivatives and removed via the urine. Paracetamol is processed via the microsomal cytochrome P-450 system, whereby potentially toxic derivatives are formed. By binding with glutathione, these can be detoxified. If this does not happen, an irreversible binding with liver cell proteins occurs. This leads to cell necrosis.

The causes of paracetamol intoxication are:

1) 50% accidental;

2) 50% suicide.

Characteristics of patients with paracetamol intoxication:

1) 50% with alcohol or drug problems;

2) 60% take antidepressants.

Laboratory tests show a very strong increase in transaminases (> 1000), an increase in creatinine and the development of metabolic acidosis. The toxicology screen on urine can show paracetamol.

Treatment consists of nasogastric lavage (if paracetamol was taken less than 4 hours before) and administration of activated charcoal (1 g/kg). Intravenous acetylcysteine ​​(glutathione donor) should be administered if liver function tests are impaired.

The combination of amoxicillin and clavulanic acid is a frequent cause of cholestatic hepatitis in the elderly. There may be an interval of several weeks between taking the medication and noticing cholestasis. Cholestatic hepatitis is associated with typical histological abnormalities.

Acute liver failure has been reported when isoniazid and rifampicin are co-administered to patients taking other enzyme inducers.

ALF manifests as jaundice with increased INR and decreased consciousness.

ALF is present when there is an increase in the INR (> 1.5) and when hepatic encephalopathy appears in a patient previously not known to have serious underlying liver disease.

The interval between the first increase in bilirubin and the onset of hepatic encephalopathy also determines the prognosis. Hyperacute liver failure is present if this interval is less than 1 week. This may be accompanied by cerebral edema and cerebral compression. If the interval is longer than 6 to 8 weeks, subacute liver failure is present. The clinical picture then corresponds to the end stage of a patient with cirrhosis, without cirrhosis being present. Mortality in this type is caused by bacterial infections.

Hepatitis A and acetaminophen cause hyperacute liver failure. Hepatitis B usually leads to acute liver failure. Liver failure provoked by DILI leads to subacute liver failure. This type is now considered the most important cause of ALF.

If the patient meets the criteria for urgent liver transplantation, he has a mortality of more than 90% within 2 weeks if he does not receive a transplant. However, if the patient recovers, a complete spontaneous recovery follows.

Scores that help to assess the need for liver transplantation include the King's College Criteria. They are based on age, etiology, the interval between the rise in bilirubin and the finding of hepatic encephalopathy, the INR and bilirubin level. The subacute forms have the worst prognosis.

Therefore, a patient without previous liver disease who develops an INR > 1.5 should be referred immediately to a centre where urgent liver transplantation is possible. In that case, supportive therapy with N-acetylcysteine ​​can be given. This results in an improvement of peripheral tissue oxygenation.

When transaminases remain elevated for more than 6 months, chronic hepatitis is present.

Chronic hepatitis B presents with chronically elevated transaminases and the presence of hepatitis B DNA. Worldwide, there are an estimated 315 million carriers. Hepatitis B is a highly contagious virus. This poses a great risk to cohabitants. It is a sexually transmitted disease, it is also transmitted from mother to child (vertical transmission) and it is also transmitted via needle stick injuries. The diagnosis is made based on the presence of hepatitis B surface antigen. Based on hepatitis B DNA and transaminase, different forms can be distinguished. One form can progress to another.

1) HBe antigen positive

2) HBe antigen negative

Chronic hepatitis B (hepatitis B antigen positive and negative forms) leads to cirrhosis after 10 years in 30% of infected patients. Carriers with high viral replication have no risk of developing cirrhosis, but from middle age onwards have an increased risk of developing hepatocellular carcinoma. Carriers with low viral replication have a very favorable prognosis. These patients are infectious. Flare-ups of the disease can occur with cytostatics and corticosteroids.

Patients with chronic active (meaning: disturbed transaminases) hepatitis B (hepatitis B antigen positive and negative form) are best treated with polymerase inhibitors (anti-viral effect). A therapy that best lasts until the hepatitis B surface antigen has become negative. However, this can take years.

Chronic hepatitis C presents with chronically elevated transaminases and the presence of hepatitis C RNA.

High risk groups include: intravenous/nasal drug users and homosexual HIV patients. The diagnosis is made by detecting hepatitis C antibodies. If these are positive, an additional hepatitis C RNA determination is indicated. If the RNA is negative, it concerns past hepatitis C. If the RNA is positive, which is accompanied by an increase in transaminases over time, it concerns chronic active hepatitis. 

Chronic HCV may be associated with extrahepatic manifestations. These include B-cell lymphomas, porphyria cutanea tarda, and vasculitis (mixed cryoglobulinemia associated with skin and renal lesions). Chronic active hepatitis C leads to cirrhosis in approximately 20% of patients after approximately 20 years, with a subsequent progression to hepatocellular carcinoma (HCC) of 2% per year. Chronic hepatitis C can be successfully treated with direct active antiviral medication; usually a combination of protease inhibitors, NS5A inhibitors and polymerase inhibitors. It is important to check whether the dose of the associated medication does not need to be adjusted (drug-drug interactions, polypharmacy).

Presents with chronically elevated transaminases and presence of anti-smooth muscle antibodies. It may also manifest as impending liver failure.

It is a rare condition, occurring in approximately 25 to 30 patients per million. It mainly affects women (75%). It can occur at any age. The diagnosis is made by means of chronically abnormal transaminases, increased gammaglobulins, more than 20 to 30g/l with specific increase in IgG, but can also present as acute liver failure. There are different types, of which type 1 is the most common. This is characterized by the presence of anti-smooth muscle antibodies. To confirm the diagnosis, a liver biopsy is needed that shows an aggressive form of hepatitis. A favorable response to steroids is a prerequisite for correct diagnosis.

The disease can be characterized by periods of normal transaminases with flares. About 30% of patients have cirrhosis at the time of diagnosis. These patients have a poorer long-term prognosis. There is an effective treatment with steroids. The treatment is usually lifelong; the therapy should be given for at least three years. If this first-line therapy fails, a second-line therapy can be used, including cyclosporine or tacrolimus.

Cholestasis means the accumulation of bile components in the liver cells, namely bile salts and possibly also bilirubin (bilirubinostasis).

Chronic cholestasis can be triggered by intrahepatic diseases. This can involve pathologies directly of the bile duct tree, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4 cholangiopathy. It can also be indirect, as a result of cirrhosis. Intrahepatic cholestasis can also be triggered by congenital conditions that are associated with impaired bile duct transport. These conditions are very rare.

Chronic cholestasis results in a deficiency of bile components in the small intestine. A decrease in bile salts can lead to malabsorption of fats, resulting in steatorrhea and a deficiency of fat-soluble vitamins. Acute cholestasis is caused by an obstruction of the large bile ducts. This can lead to painful jaundice, which is mainly caused by choledocholithiasis, or painless jaundice, usually due to malignancy. This is accompanied by dark urine and pale stools. Cholestasis is accompanied by a build-up of bile components in the blood, which causes itching. There can also be an increase in bilirubin, which leads to jaundice (icterus).

The bilirubin increase in cholestasis consists of a combination of unconjugated (indirect) and conjugated (direct) bilirubin. An exclusive increase in unconjugated bilirubin occurs in hemolysis, in which there is an excessive production of bilirubin, which can no longer be conjugated. It also occurs in Gilbert's syndrome. This is characterized by an isolated increase in unconjugated bilirubin, without an increase in the other liver tests. This is a genetic conjugation disorder of bilirubin, which does not give rise to any disease picture and can be detected by searching for a single-gene mutation.

Itching (pruritus) is a typical feature of cholestatic liver disease. This complication is very difficult to treat. Reasons for treatment are nocturnal itching and scratching lesions. The treatment of pruritus consists of anti-itch lotions and colestyramine, a resin that binds bile salts in the intestines and therefore must be given four hours apart from taking other medication. It works mainly for mild forms of itching. Rifampicin is usually prescribed, but this can cause hepatotoxicity in about 5% of patients. In case of jaundice it leads to vitamin K deficiency. Itching can sometimes be an indication for liver transplantation. There is no place for antihistamines because they are not effective here and can only increase fatigue.

Typically presents in middle-aged women with chronic cholestasis, pruritus, and positive anti-mitochondrial factors.

Primary biliary cholangitis (PBC, formerly called primary biliary cirrhosis) is a rare, potentially life-threatening liver disease. The disease primarily affects women between the ages of 50 and 70 at diagnosis, but can also occur in younger women and men.

This involves progressive destruction of the small interlobular bile ducts in the portal fields. This subsequently leads to increased concentrations of bile acids in the liver cells, later to liver fibrosis and finally to biliary cirrhosis. This damage would be chemically caused by cholangiocytes excreting insufficient bicarbonate. Bicarbonate protects bile ducts from damage.

The disease is characterized by fatigue (80%) and pruritus (50%). It can be associated with other organ pathology, such as sicca syndrome, arthralgia and autoimmune thyroiditis.

Serious clinical complications occur in these patients in approximately 15% of cases respectively. After 5 to 10 years this can increase to 30%. However, this evolution is very variable and after 20 to 30 years patients can still show few symptoms.

Risk groups for a more aggressive course are young women and men. The level of alkaline phosphatases is one of the best independent predictors of the patient's prognosis.

The diagnosis is made on the basis of the increase in alkaline phosphatases and gamma-GT, together with the increase in IgM immunoglobulins and autoantibodies against mitochondria (anti-mitochondrial factors > 1/40). A distinction is made between an anti-mitochondrial positive and negative form. The latter is rather rare. The antibodies anti-sp100 and anti-gp210 are also very suggestive of PBC. The biopsy is suggestive.

In case of severe fatigue the following diseases should be excluded:

- hypothyroidism;

- celiac disease;

- pernicious anemia.

There is an effective treatment, namely ursodeoxycholic acid 13-15 mg/kg/day. About one third of patients do not respond to this therapy. As second-line therapy obeticholic acid and fibrates are used today.

Chronic cholestasis can cause osteopenia in middle-aged women, who are already at increased risk for osteoporosis. These patients should receive calcium and vitamin D supplements.

Presents as chronic cholestasis, especially in young men, associated with chronic inflammatory bowel disease.

It is a rare disease. This involves chronic inflammation of the large hepatic bile ducts, as well as the intrahepatic bile ducts. This causes fibrosis and biliary strictures.

The disease occurs mainly in young men. More than 70% of patients with PSC have inflammatory bowel diseases, such as ulcerative colitis.

The diagnosis is made on the basis of a chronic increase in alkaline phosphatases and gamma-GT. An MRI scan of the bile ducts, or MRCP, typically shows stenosis and small pearl-shaped dilatations. The liver biopsy is also suggestive.

The disease is mainly complicated by recurrent cholangitis. Approximately 8% of patients develop cholangiocarcinoma (1% per year). Isolated short strictures are suspicious for cholangiocarcinoma and patients have an increased risk of gallbladder cancer.

The disease can slowly progress to an end-stage of biliary cirrhosis. Since these patients can be transplanted systematically, the main causes of death are now not so much liver failure, but colorectal and hepatobiliary tumors (including gall bladder tumors).

There are 2 types of PSC:

- large duct PSC, the most common form;

- small duct PSC, in which there are no abnormalities of the extrahepatic bile ducts.

A distinction must be made with the rarer forms of sclerosing cholangitis, such as ICU cholangiopathy or biliary strictures after liver transplantation, due to ischemia of the bile ducts. There is no recognized therapy for PSC. Biochemical improvements are noted with ursodeoxycholic acid. In cholangitis, endoscopic balloon dilations of the stenosis in the choledochus should be performed. In case of recurrent cholangitis and liver decompensation, PSC is an indication for liver transplantation.

Presents as pseudotumors of the bile ducts.

IgG4-associated cholangiopathy belongs to the IgG4-induced system pathology. It occurs mainly in older men, with a history of exposure to solvents. It usually presents as a cause of painless jaundice. Another manifestation is IgG4-associated pancreatitis. In 75% of cases, there is a serum IgG4 value four times above the normal value. On MRCP, there are long thickenings of the choledochus with narrowing. The differential diagnosis must be made with PSC and cholangiocarcinoma. It can present as a tumor of the bile ducts (pseudotumor).

The current treatment consists of prednisolone, combined with azathioprine. This is given for at least 12 weeks. Relapse is frequent, which results in lifelong treatment in some patients.

There may be an overlap between AIH and PBC or AIH and PSC. The conditions may co-occur or one form may evolve into the other: from autoimmune hepatitis in childhood to primary sclerosing cholangitis in adulthood. These variants are treated with corticosteroids-azathioprine and ursodeoxycholic acid.

Presents with increased Fe saturation and ferritin.

Approximately 60% of our body iron (Fe) is located in the hemoglobin of the red blood cells. Most of the Fe in the plasma comes from the release from the macrophages of the reticulo-endothelial system. A smaller part comes from the gastro-intestinal system. The two most important Fe-binding proteins in the serum are transferrin and especially ferritin. Hepcidin is a small protein that is produced by the liver parenchymal cells, in response to a disturbed Fe balance and/or to an inflammatory stimulus. The regulation of hepcidin is partly determined by, among other things, the HFE protein. With a high plasma Fe, hepcidin is stimulated, which suppresses the secretion from the macrophages, and there is a reduced absorption from the intestine.

This condition is caused by a mutation in the HFE gene. This gene codes for the protein that modulates hepcidin, which regulates iron absorption in the intestine. It usually involves a mutation from cysteine ​​to tyrosine in amino acid 282 (C282Y mutation). In addition to this classic form, there are other very rare types.

Patients present with fatigue, arthralgia and increased transaminases. On clinical examination the gray-brown skin color is conspicuous. Associated with liver disease may develop diabetes, myocardial infiltration (rhythm disturbance) and chondrocalcinosis (arthralgia).

The diagnosis is made by a Fe saturation of more than 65% (normal saturation less than 45%) and an increase in ferritin, for example 1000 micrograms/dl (normal level: less than 250 micrograms per dl). The definitive diagnosis is made by looking for the gene mutation.

In making the diagnosis, a family screening must be done by detecting the gene mutation. The treatment consists of phlebotomy (bloodletting) with the aim of serum ferritin < 100mg/l.

This disease is caused by mutations that lead to copper accumulation in the liver (excretory disorder) and the brain. This results in neuropsychiatric symptoms and movement disorders. The diagnosis is made by the presence of a very low serum ceruloplasmin level (plasma copper binding protein), increased copper excretion in the urine (> 100 pg/24 hours) and by the presence of copper accumulation at the edge of the cornea, the so-called Kayser-Fleischer ring.

Patients may also present with acute liver failure (ALF) in which unconjugated bilirubin is markedly elevated. This is due to the release of copper from the tissue, which leads to hemolysis. Familial screening should be performed by detecting the gene mutation. The treatment aims to bind copper and increase urinary excretion. For this purpose, D-penicillamine (750 to 1 g/day) is used with supplements of pyridoxine (vitamin B6) (250 mg/week).

This is a congenital abnormality in the structure of the alpha-antitrypsin produced, such that the aberrant isoenzyme is not excreted from the liver cell. The accumulation in the hepatocytes gives rise to neonatal cholestasis in the newborn. In adulthood it gives rise to cirrhosis, but together with alcohol can cause premature development of cirrhosis.

Plasma deficiency can lead to early emphysema at the age of 18 to 30. The diagnosis is made by the dosage of the alpha-1-antitrypsin protein. However, this is usually increased secondary to cirrhosis. The diagnosis is also made by staining the aberrant enzyme in the hepatocyte on liver biopsy and ultimately detecting the gene mutation. There is currently no specific therapy. A smoking ban should be imposed and prevention of lung infections is important. In case of symptomatic cirrhosis, a liver transplant should be performed.

Porphyrias are a group of metabolic diseases caused by a dysfunction or defect in one of the enzymes of heme biosynthesis. This leads to the accumulation of toxic heme precursors. There are genetic and acquired forms. The most common form is porphyria cutanea tarda. It occurs in 0.5 to 1 in 10,000 cases. The pathogenesis is caused by the accumulation of porphyrins in the liver and is further provoked by various factors, such as alcohol and oral contraception. Typical are sunlight toxicity of the skin and dark red urine if it has been in the urethra for a while. Biochemically there is an increased iron saturation and increased ferritin. The treatment consists mainly of avoiding provoking factors. In case of iron overload, bloodletting must be performed (chelation).

There is a whole list of rare hereditary disorders that affect the liver and are called 'metabolic' diseases. These are diseases in which something goes wrong in the metabolism due to a genetic defect. This can be in the production, combustion or storage of sugars (glycogenesis), in the processing of amino acids (for example tyrosinemia), in the production, storage or processing of fats and in the breakdown of old cells and their membranes (Gaucher disease).

This concerns alcoholic and non-alcoholic liver disease.

Alcohol abuse is one of the leading causes of liver disease in the West. Alcohol abuse does not lead to liver disease in everyone, but the risk of cirrhosis increases the longer and the more alcohol is consumed. Recent guidelines speak of problematic alcohol use when someone consumes more than 10 units of alcohol per week, where a unit is approximately 10g of ethanol. This is the equivalent of one glass of lager, one glass of wine or a shot of spirits.

Alcohol abuse can affect other organs besides the liver and cause the following diseases: acute and chronic pancreatitis, polyneuropathy, gout, cardiomyopathy, neurological disorders such as Korsakoff syndrome (confabulations with memory disorders) and Wernicke syndrome (confusion with ataxia and impaired eye coordination). Finally, alcohol abuse gives an increased risk of oral, pharyngeal, laryngeal and esophageal carcinomas, especially if the patient also smokes.

The damage of alcohol to the body occurs according to various factors, such as race and gender. For example, the Japanese quickly form an increased concentration of acetaldehyde, which leads to 'flushing'. Alcohol is more harmful to women for several reasons:

- alcohol is not fat-soluble and women have more fat mass. As a result, they have a smaller volume of distribution, which allows them to reach high blood alcohol concentrations more quickly;

- women have less alcohol hydrogenase;

- estrogens have a synergistic effect on oxidative stress and inflammation.

There is also an increased risk of developing alcoholic cirrhosis after gastric bypass, due to the reduced alcohol dehydrogenase activity in the stomach and underlying non-alcoholic fatty liver disease. Prevention is extremely important, alcohol abuse must be detected early and actively recognized. Specific questionnaires have been developed for this (CAGE and AUDIT-C).

There are currently no good routine tests to detect chronic alcohol abuse. The alcohol levels found in the blood during blood tests and/or breath tests quickly become negative. The most accurate technique is to detect alcohol metabolites (ethyl glucuronide) in the hair, which give an idea of ​​the alcohol abuse in the past three months. In the urine they give an idea of ​​the alcohol intake in the last few days. There are different stages of alcohol abuse. Abuse occurs in 20% of the population. The person involved then suffers on a physical, social and mental level. 5% of the population has an addiction, which is characterized by tolerance (having to drink more and more to get the same effect) and withdrawal symptoms.

Delirium tremens

Delirium tremens is a withdrawal symptom. It usually occurs within 6 to 24 hours to 5 days after stopping alcohol. It makes the patient very anxious and irritated. It is accompanied by hallucinations and leads to serious restlessness. Clinical examination reveals a rapid, fine tremor. This can lead to epilepsy and coma. Today, treatment consists of placing the patient in a quiet (dark) room and administering tranquilizers. The following are used: diazepam (10 mg/4 to 8 hours), clorazepate (three times 10 to 20 mg/day) or haloperidol (5 to 10 mg intramuscularly or intravenously, then 1 to 10 mg/day depending on agitation). If glucose is given by infusion, 10 g of vitamin B1 is added. There is currently no adequate medication for alcohol dependency in patients with advanced liver disease. Disulfiram is contraindicated in cirrhosis. There is little experience in patients with cirrhosis with other products, acamprosate or naltrexone.

Presents with increased gamma-glutamyltransferase (gamma-GT) and an enlarged hyperreflective liver on ultrasound.

Alcohol abuse leads to steatosis in the liver (accumulation of triglycerides in hepatocytes). This condition causes few symptoms. Clinical examination reveals a large, fairly soft liver. The lab suggests alcohol abuse: increased gamma-GT, increased MCV (volume of erythrocytes), increased triglycerides and an increase in uric acid. There will be more aspartate aminotransferases than alanine aminotransferases (AST > ALT). A large hyperreflective liver is found on radiology.

In the differential diagnosis of hepatic steatosis, the following conditions must be excluded:

- non-alcoholic fatty liver disease (NAFLD)

- unbalanced parenteral nutrition;

- malnutrition due to anorexia nervosa;

- bariatric surgery by means of jejuno-ileal short-circuiting;

- medically indicated conditions (including corticosteroids and cordarone);

- acute gestational steatosis.

The prognosis is favorable after stopping alcohol and the abnormalities can disappear after six weeks.

Presents with a marked increase in y-GT, accompanied by jaundice and an enlarged hyperreflective liver.

ASH occurs in a third of heavy drinkers and is usually already superimposed on alcoholic cirrhosis.

The symptoms and biochemistry are determined by the severity of the alcoholic static hepatitis. A severe form is characterized by:

- chachexia;

- icterus;

- leukocytosis and a low platelet count (also due to suppression by alcohol);

- a moderately increased amount of transaminases: about 100 IU/l;

- AST > ALT;

- very high y_GT, as well as Fe saturation and ferritin (differential diagnosis with primary hemochromatosis).

The prognosis is unfavorable if the Maddrey score is higher than 32. This is based on the prothrombin time (PT) and the amount of bilirubin. The patient can then evolve into acute or chronic liver failure.

Treatment consists of: stopping alcohol, preventing delirium tremens, administering vitamin B1 and providing sufficient calorie-rich food (enteral nutrition if necessary). If the Maddrey score is higher than or equal to 32, prednisolone must be administered for one month, to be stopped if the Lille score does not decrease after one week. This score is based on, among other things, the amount of bilirubin.

Presents with abnormal liver tests in patients with metabolic syndrome.

Non-alcoholic fatty liver disease is a manifestation of the metabolic syndrome, which is characterized by:

- abdominal obesity (waist circumference >= 94 centimeters for men and >= 80 centimeters for women);

- insulin resistance (fasting glycemia >= 110);

- hyperlipidemia;

- arterial hypertension.

The pathophysiology is complex. It involves an overload of the adipose tissue (especially visceral), which leads to a dysfunction of this adipose tissue. This results in the release of free fatty acids, which accumulate in the hepatocytes and are converted into triglycerides, which overload the hepatocytes. The patients are usually free of complaints. The diagnosis is therefore made on the basis of routine laboratory tests. This mainly involves an increase in y-GT, with or without a slight increase in transaminases and alkaline phosphatases. Biochemically, an isolated increase in serum ferritin is found in a number of these patients. An enlarged hyperreflective liver can be seen on an ultrasound.

Two stages are distinguished:

- non-alcoholic steatosis: does not lead to complicated liver disease;

- non-alcoholic steatohepatitis (NASH): can lead to cirrhosis in 20% of patients after 20 years.

The distinction is made using a liver biopsy.

Presents as acute abdominal pain or upper gastrointestinal bleeding without underlying cirrhosis.

Venous thrombosis generally occurs due to blood stasis (by local factors) and prothrombotic disorders.

Local risk factors for portal vein thrombosis without cirrhosis are perinatal umbilical infections and pancreatitis. In the latter situation it leads to a thrombosis of the vena lienalis. It can also be provoked by a splenectomy.

The prothrombotic abnormalities can be acquired, among other things as a result of an underlying myeloproliferative disorder (detectable via JAK2 mutations). They can also be caused by congenital deficiencies, such as protein S deficiency, protein C deficiency, factor V Leiden and mutations in the prothrombin gene. An additional risk factor is oral contraception. In 50% of cases there is more than one risk factor. The clinic of an isolated portosplanchnic venous thrombosis is a coincidental finding, in a third of cases abdominal pain (due to venous congestion) and signs of systemic inflammation and esophageal varices bleeding. Because the liver is also supplied by the hepatic artery, no ischemia of the liver occurs.

The diagnosis is made using a Doppler examination of the liver. An old thrombosis gives a cavernous transformation of the portal vein. Rarely, a portal cholangiopathy develops due to compression of the collaterals on the choledochus.

Since the systematic anticoagulation of these patients, the five-year survival rate has increased to over 90%. Mortality can occur due to an intestinal infarction, especially when the mesenteric vein is also thrombosed.

Screening for esophageal varices should be performed.

Presents as a sudden onset of painful enlarged liver and formation of ascites.

In these conditions there is a disturbed venous drainage of the liver due to compression thrombosis in the large hepatic vein.

The syndrome is usually caused by a thrombosis in the hepatic veins. In 80% of cases the cause is a consequence of prothrombotic abnormalities (acquired or congenital deficiencies, the same risk factors as for portal vein thrombosis). In 50% there are several factors that play a role simultaneously. Very rarely the venous drainage is obstructed by a web in the vena cava.

Budd-Chiari syndrome usually presents acutely, with sudden, severe and painful hepatomegaly and the development of ascites. In this situation, the three hepatic veins are usually thrombosed.

In 15% of cases, there is also a portal vein thrombosis.

The diagnosis is made by means of an ultrasound, a CT or an MRI scan, where the hepatic veins are no longer demonstrable, together with perfusion disorders in the liver. There is usually a hypertrophy of the lobus caudatus, because it has a separate blood drainage, which is less likely to thrombose. The swollen liver gives compression on the vena cava. The ascitic fluid shows a high protein and albumin content.

The patient must be anticoagulated for life, even in the presence of esophageal varices and also after liver transplantation. If a hepatic vein is still open, venous drainage can be improved by angioplasty or transjugular intrahepatic portosystemic shunt (TIPS). In some cases, urgent liver transplantation is necessary.

In these conditions, there is impaired venous drainage from the liver, due to occlusion in the small hepatic venules, by damage to the endothelium of the sinusoids. It occurs in a graft-versus-host disease after bone marrow transplantation, or in response to certain cytostatics.

It is clinically characterized by icterus, tender hepatomegaly and ascites. It has a poor prognosis.

This is a congenital familial disease (autosomal dominant with a prevalence of 1 to 2 in 10,000), in which arterio-venous shunts develop in the liver. This can cause local ischemia in the liver, mainly in the bile ducts and gallbladder. The large AV shunts in the liver can also lead to a 'high output failure' of the heart.

The disease is characterized by frequent nosebleeds and the characteristic vascular abnormalities of the lips, nose and fingertips.

In case of liver-biliary ischemia and/or to prevent heart failure, a liver transplant is indicated.

This condition is rare and has different names in the literature (hepatoportal sclerosis, non-cirrhotic portal fibrosis, incomplete septal cirrhosis, nodular regenerative hyperplasia).

As a result of phlebosclerosis of the portal vein, there is a perfusion disorder of the liver. It is usually associated with immunological and systemic diseases, use of medication such as azathioprine, HIV medication and thrombophilic diseases. Non-cirrhotic portal hypertension is frequently found in cystic fibrosis (as a result of precipitation of bile in the small bile ducts).

It gives portal hypertension which usually manifests itself in the form of a greatly enlarged spleen and esophageal varices. On an ultrasound there are signs reminiscent of cirrhosis such as noularity of the liver parenchyma, but an elastography measurement gives values ​​< 10 kPa.

An increased incidence of portal vein thrombosis is found. The short-term prognosis is good (normal liver synthesis capacity), but it can evolve into chronic liver failure and the need for liver transplantation.

Fibrosing

Tissue may show unwanted scarring. Fibrosing means the formation of an excessive amount of scar tissue in organs or tissues during a reparative process. Tissues that are normally separated by membranes and sliding layers can stick together by collagen formation. This leads to annoying movement restrictions if no functional treatment is given.

In liver cirrhosis due to alcoholism, chronic inflammatory processes are the cause of fibrosis. The formation of 'advanced glycation endproducts' (AGEs) in diabetes patients also leads to tissue stiffening and to movement restrictions. In inflammatory processes, fibroblasts tend to randomly produce connective tissue if the repair process goes awry.

The pathogenesis is an embryonic ductal plate malformation, which leads to dilatations of the bile duct tree. Different types are distinguished. 

Types where there is no communication with the bile duct:

- biliary hamartomas: diffuse small (less than one centimeter) biliary cysts. The condition is benign and does not cause any symptoms. The radiological image can be confused with liver metastasis.

- polycystic liver diseases

Types in which there is permanent communication with the bile duct (large bile ducts):

- choledochal cysts;

- Caroli's disease or syndrome: This concerns isolated dilatations of the large intrahepatic bile ducts, which can lead to cholangitis. In the case of Caroli's syndrome, this is accompanied by congenital liver fibrosis and autosomal recessive polycystic kidney disease. In that case, there is a risk of portal hypertension, which can be complicated by esophageal varices.

Presents with marked hepatomegaly with multiple cysts.

Polycystic liver diseases are part of the autosomal dominant polycystic kidney diseases. These are genetic disorders of the cholangiocytes, which increase cell proliferation and secretion of these cholangiocytes and thus give rise to the development of biliary cysts. Rarely, the cysts are isolated in the liver, in which case it is autosomal dominant polycystic liver disease. Symptomatic PCLD occurs mainly in middle-aged and younger women. At least 10 large liver cysts are involved and the disorder is associated with cerebral aneurysms and mitral valve prolapse. The liver cysts may be complicated by bleeding or infection (mainly after previous kidney transplantation) or by marked hepatomegaly (> 5 liters) with secondary compression on the other organs. Treatment consists of stopping estrogens and administering somatostatin analogues. These inhibit bile secretion in the cyst and reduce the volume. In extreme hepatomegaly with the need for continuous analgesia and in the development of malnutrition, a liver transplant is indicated. In case of associated renal insufficiency, this should be done simultaneously with a kidney transplant.

Liver cirrhosis is an end stage of chronic liver disease and can remain asymptomatic and ignored for a long time. Liver disease is not painful.

The diagnosis is suspected on clinical examination, which may reveal the following abnormalities:

- stellate angiomas or spider naevi;

- palmar erythema;

- clubbing of fingers;

- gynecomastia;

- testicular atrophy;

- gynecoid hair distribution (patients develop sexual dysfunction due to testosterone deficiency).

Cirrhosis has the following characteristics:

- the occurrence of muscle atrophy, mainly visible in the upper limbs;

- collateral circulation in the abdominal wall;

- bumpy liver (initially enlarged and later reduced in the ind phase), splenomegaly (larger than 12 centimeters), ascites;

- edema of the lower limbs;

- flapping tremor;

- foetor hepaticus (a musty penetrating odor due to hepatic encephaloparrhythmia).

In the lab, high gammaglobulins are noticeable (with beta-gamma bridge formation on electrophoresis), low albumin, high INR and increased bilirubin. The blood picture shows thrombocytopenia due to decreased production as a result of decreased thrombopoietin and by hypersplenism via portal hypertension. Sometimes, in severe alcoholic cirrhosis, it shows spur-cell anemia, by the appearance of acanthocytes (red blood cells with an aberrant shape, which hemolyze easily).

The sonographic signs of advanced liver disease are irregular contours of the liver, venous collaterals, splenomegaly, ascites and narrowing of the hepatic veins. Active screening for portal vein thrombosis or hepatocellular carcinoma (HCC) should be performed on the sonography.

Using a fibroscan, an elastography measurement can be performed. A value of <5 kPa excludes fibrosis, a value of <10 kPa excludes cirrhosis, a value of <15 kPa excludes advanced cirrhosis and a value of <20 kPa indicates cirrhosis with a high risk of complications. Fibroscan measurements are possible in 80% of patients. It is not possible in obesity, among other things.

The gold standard for diagnosing cirrhosis is a liver puncture. This is done percutaneously. However, when the platelets are low and the INR is elevated, or in the case of liver congestion, there is a risk of bleeding and the biopsy must be done via the transjugular route.

Complications of cirrhosis include portal hypertension, impaired liver synthesis capacity, and an increased risk of bacterial infections. When these complications occur gradually, it is called decompensated cirrhosis. When there is rapid progression to multi-organ failure, it is called acute on chronic liver failure. Finally, patients with liver cirrhosis have a very high risk of developing hepatocellular carcinoma (HCC).

The severity of liver disease was previously mainly assessed using the so-called Child-Pugh score. This score is determined by the presence of ascites, hepatic encephalopathy, severity of jaundice, severity of hypoalbuminemia and severity of the disturbed PT. Three groups are distinguished: Child A (best prognosis), Child B and Child C (worst prognosis). The Child-Pugh score was previously developed to estimate the mortality of a laparotomy (Child A: <5%, Child B: 25% and Child C: 50%).

The most objective score that is mainly used today is the MELD score. It is based on the INR, bilirubin and creatinine. The score ranges from 6 to 40. It gives a very accurate estimate of short-term survival in most causes of cirrhosis.

Another prognostic score is the frailty index. Weakness occurs in 30 to 40% of patients with cirrhosis. This weakness is caused by malnutrition and muscle wasting and determines the prognosis. For cirrhosis patients, there is a specific liver frailty index (Liver Frailty Index). This consists of the results of grip strength, the ability to 'sit' and a balance test.

Since most coagulation factors are produced by the liver (with the exception of factor VIII and von Willebrand factor) and cirrhosis causes thrombocytopenia and platelet dysfunction, patients with cirrhosis are at risk for coagulation problems. In cirrhosis, over time, a balance between procoagulant and anticoagulant factors usually develops.

Initially, there is an increased tendency for thrombosis, which causes 15 to 20% of patients with advanced cirrhosis to develop a portal vein thrombosis. This increased tendency for thrombosis causes microthrombi to form in distal branches of the portal veins. This leads to perfusion disorders in the liver and increases liver failure.

In more advanced forms of cirrhosis associated with infections, an increased tendency to bleed may eventually develop. An increased PT (INR) does not indicate an increased risk of bleeding, but is rather a parameter of the severity of the underlying liver disease.

ACLF occurs in 30% of patients who need to be hospitalized. It mainly concerns patients with underlying cirrhosis, who rapidly progress to multi-organ failure (renal failure, hepatic encephalopathy, coagulopathy, liver failure characterized by a very sharp increase in bilirubin, respiratory failure). In 50% of patients there is no direct provoking factor. The pathogenesis is increased permeability of the gastrointestinal tract to bacterial toxins (due to a disturbed intestinal microbiome/virion, including direct alcohol toxicity). Acute or chronic liver failure is initially characterized by a cytokine storm, accompanied by cholestasis and severe jaundice, as in sepsis. Subsequently, immune paralysis develops, leading to bacterial infections and eventually multi-organ failure.

Patients with acute or chronic liver failure may also develop relative adrenal insufficiency (hepatorenal syndrome). The prognosis can be estimated using the CLIF scores. The complication has a mortality of approximately 60% after 6 weeks. There is no therapy yet.

Portal hypertension can be divided into cirrhotic and non-cirrhotic portal hypertension. Portal hypertension indicates an increase in hydrostatic pressure in the portal vein. 

There are several possible causes for this:

1) presinusoidal: for example a portal vein thrombosis or an intrahepatic cholestatic liver disease, due to interaction-inflammatory small bile ducts and small portal venules;

2) sinusoidal: due to cirrhosis, severe alcoholic steohepatitis or tumoral infiltrations;

3) post-sinusoidal: due to a disorder of the venous drainage of the liver, as seen in Budd-Chiari syndrome, pericarditis constructiva or chronic heart failure. This can lead to cardiac cirrhosis.

The increased portal pressure in these cases is caused by an increased intrahepatic vascular resistance. This resistance is caused by a non-manipulable component, namely fibrosis, and by a drug-manipulable component, namely the development of contractile myofibroblasts by activation of stellate cells. These myofibroblasts cause an increased vascular resistance by a deficiency of nitric oxide (NO). On the other hand, there is a decreased extrahepatic systemic vascular resistance, caused by an excess of NO. As a result, there is an increased splanchnic* inflow: an attempt to maintain liver perfusion. This increased inflow then leads to the maintenance of flow in the collaterals. Clinically this phenomenon manifests itself by an increased cardiac output, a systemic underfilling and a low blood pressure with an increased pulse.

[*splanchnic circulation' describes the blood flow to the abdominal gastrointestinal organs including the stomach, liver, spleen, pancreas, small intestine, and large intestine. ]

In the serum thrombocytopenia is found (hypersplenism). Later this also has a decrease in white and red blood cells, with an active bone marrow. The radiological indirect signs of portal hypertension are collaterals, splenomegaly and ascites, found on ultrasound.

Consequences of portal hypertension include: 

1) esophageal varices bleeding; 

2) ascites and complications; 

3) hepatic encephalopathy; 

4) other rare complications of portal hypertension.

Presents with upper gastrointestinal bleeding in a patient with indirect signs of cirrhosis.

Esophageal varices are venous collaterals that arise from the portal vein due to portal hypertension. Bleeding occurs due to rupture due to the overpressure and because there is no counterpressure from the surrounding tissue. They protrude into the lumen of the esophagus. The varices are usually located in the distal 5 centimeters of the esophagus. They cause hematemesis and/or melena.

Diagnosis is made by esophagoscopy, where esophageal varices can be visualized directly. In 20% of bleeding in a patient with cirrhosis, the cause is not esophageal varices, but among others Mallory Weiss, ulcer, etc.

When esophageal varices are diagnosed, one third of patients will bleed within two years. Signs of a high risk of rupture are large varices and the presence of red spots in the varicose wall, as an expression of thinness of the wall.

Without therapy, the mortality of a first hemorrhage is 20 to 50%, depending on the remaining liver function. If a recurrence of bleeding occurs, this is in 40% of cases within six weeks with a mortality of 40%. If correct treatment is instituted, the mortality at that time is reduced to less than 10%.

Given the high risk of rupture of esophageal varices, preventive measures should be taken in the presence of large varices. This therapy consists of non-selective beta-blockers (propranolol type) or carvedilol (+ alpha-receptor blocker). Carvedilol is not indicated in hypotension and renal insufficiency. The selective beta-blocker reduces the splanchnic inflow, which reduces portal hypertension.

If there is a contraindication for beta-blockers, ligatures should be placed as a preventive measure.

If esophageal varices bleeding is suspected, the patient should be transferred to a specialized hospital quickly. General measures for upper gastrointestinal bleeding should be initiated, such as protecting the airway against aspiration pneumonia and treating hypovolemic shock with blood transfusions. Fluid overload maintains the bleeding and blood transfusions are only indicated from a hemoglobin < 7g/dl.

If upper gastrointestinal bleeding due to esophageal varices is suspected, somatostatin or terlipressin should be administered immediately. These products reduce portal pressure by vasoconstriction of the splanchnic arterioles.

If esophageal varices are found, they should be treated with rubber band ligatures. To accelerate gastric emptying and thus prevent aspiration pneumonia, erythromycin IV can be administered half an hour before endoscopy. High intestinal bleeding in a cirrhotic patient is associated with a high risk of bacterial infection. Therefore, antibiotics should be started systematically.

When someone has bled, secondary prevention must absolutely be instituted. That is the combination of the non-selective fatty blocker together with eradication of the varicose veins by rubber band ligatures.

In some circumstances, a transjugular intrahepatic portosystemic shunt (TIPS) must be created. In this case, a dilatable endoprosthesis is introduced via the jugular vein into one of the hepatic veins. The endoprosthesis is advanced to the portal vein, creating an intrahepatic shunt. This is the most efficient way to reduce portal hypertension. TIPS placement is indicated in case of esophageal varices in the following circumstances:

- in a patient with advanced cirrhosis (Child C);

- when drug and endoscopic therapy fails;

- in secondary prevention after repeated bleeding.

Creation of an intrahepatic shunt provokes hepatic encephalopathy in at least 20% of patients.

In portal hypertension, a mosaic or snakeskin appearance of the gastric mucosa is frequently seen endoscopically, especially in the corpus and fundus. It may lead to silent blood loss and therapy-resistant iron-free anemia. This creates a need for regular intravenous iron administration.

Gastric dome varicose veins are caused by left-sided portal hypertension. These are venous collaterals, originating from the vena lienalis and protruding into the fundus of the stomach. In case of bleeding gastric dome varicose veins, tissue glue should be used.

Ascites refers to the presence of an abnormal amount of fluid in the abdomen. It is the main complication of portal hypertension. In 60% of patients, it develops within 10 years. Ascites has a mortality of 50% after 8 years.

Ascites is caused by a decrease in osmotic pressure, which is caused by hypoalbuminemia and an increase in hydrostatic pressure, which is caused by portal hypertension. This causes a transition of fluid from the splanchnic venous system, the endothelium only allows water to pass through and the ascitic fluid is poor in protein. In post-sinusoidal portal hypertension, there is also a loss of proteins through the sinusoids, which have fenestrations. This gives rise to protein-rich ascitic fluid.

Portal hypertension is characterized by a relative underfilling (by peripheral vasodilation) and by the loss of fluid and proteins in the peritoneum. This results in a further systemic underfilling. This gives rise to reflex fluid retention in the kidneys. This fluid retention activates the renin-angiotensin-aldosterone system, resulting in sodium retention. Therefore, treatment with an aldosterone antagonist, such as spironolactone, is a responsible therapy for ascites.

During the clinical examination, the central venous pressure must always be measured to rule out right heart decompensation. This condition also causes malleolar edema. On inspection, the abdomen swells, the flank sags, there is diastasis of the recti muscle, skin striae develop and the umbilicus stretches sideways ('smiling umbilicus'). Skin edema and malleolar edema can also develop due to hypoalbuminia. Percussion and palpation reveal a shifting dullness in the flanks ('shifting dullness') and the iceberg sign ('signe de glaçon'). Pronounced ascites can be associated with an umbilical hernia. The diagnosis is confirmed by means of an ultrasound. This is particularly useful in people with obesity.

In patients with ascites who are admitted to the emergency department, a paracentesis should always be performed. This paracentesis should be performed in the left iliac fossa, because there is the least chance of puncturing the small intestine. The following determinations should be made on the ascites fluid:

- albumin: to establish the diagnosis;

- leukocytosis and cultures (on hemoculture bottles): to rule out spontaneous bacterial peritonitis.

The best parameter to detect the cause of ascites is the serum albumin minus the ascites-albumin difference (SAAG). If this has a value of higher than 11g/l, there is a high probability that the ascites is caused by portal hypertension due to classical cirrhosis. Cardiac ascites is characterized by the presence of many proteins.

Differential diagnosis of ascites:

- portal hypertension (80%);

- ovarian neoformations and/or peritoneal metastasis;

- peritoneal irritation including pancreatitis;

- cardiac causes (including constrictive pericarditis and cardiac decompensation, which is accompanied by increased central venous pressure);

- nephrotic syndrome, which is accompanied by diffuse edema and albuminuria.

The ascitic fluid should not be treated too aggressively ('go low, go slow'). A weight loss of half a kilogram per day is ideally aimed at, to prevent further hypovolaemia and secondary pre-renal renal insufficiency.

Phase 1 of the treatment consists of a low-salt, high-protein diet and the administration of diuretics: currently spironolactone and furosemide, with regular monitoring of electrolytes and creatinine. Attention should be paid to the side effects of the diuretics: hyponatremia (dilution), which occurs in 30% of hospitalised patients, hyperkalaemia due to spironolactone, gynaecomastia due to spironolactone and calf cramps.

Measures to be taken in case of hyponatremia: rapid normalization indicates brain damage (hypernatremia can be provoked by lactulose enemas). Initially, diuretics are stopped. Underfilling is treated with human albumin and, if necessary, terlipressin (starting with 0.5 mg intravenously in a bolus, 4 to 6 hours), to treat systemic hypotension.

In phase 2 of the treatment, in case of insufficient effect of the diuretics, paracentesis can be performed regularly. However, if >= 5 liters of ascitic fluid are drained, this must always be accompanied by administration of albumin (8 grams per liter of ascitic fluid removed), to prevent the hepatorenal syndrome. As many as 5 to 10% of patients do not respond to this treatment.

Finally, in phase 3, in patients with therapy-resistant ascites, TIPS should be considered in patients without contraindications. Then, the need for paracentesis disappears in 85% of patients, but 30% develop hepatic encephalopathy.

In patients with a MELD score higher than 19, there is a high risk of liver failure, due to increased hypoperfusion of the liver and hepatic encephalopathy due to increased shunting. This procedure is therefore contraindicated in patients with poor liver function and/or pre-existing hepatic encephalopathy. If this does occur, a reduction stent can be placed in the TIPS stent.

Presents as a patient with ascites and general deterioration. On clinical examination, peritoneal irritation is not very pronounced and the diagnosis is made by means of a puncture of the ascitic fluid. This ascitic fluid is cloudy, rich in cells and contains leukocytes: > 500/mm2, of which > 250/mm2 granulocytes. Culture of the ascitic fluid yields, among other things, E.coli. If various pathogenic bacteria are present in the ascitic fluid, this may indicate secondary bacterial peritonitis (including a perforated appendix).

If cytosis is present in the ascitic fluid, antibiotics must be started immediately, for example a third-generation cephalosporin or quinolone. Afterwards, secondary prevention with peroral antibiotics (type quinolone) is necessary until the ascites disappears.

Presents as a patient with ascites with increased creatinine. This is an increase in serum creatinine in a patient with ascites. Because patients with cirrhosis have little muscle mass, a small increase in creatinemia is already significant, namely an increase in creatinine in 24 hours greater than or equal to 0.3 mg/dl or an increase greater than or equal to 50% of the basal value. This is a functional renal impairment due to the reduction in the effective arterial blood volume with reflex vasoconstriction in the cortex of the kidney. The fact that the hepatorenal syndrome disappears after liver transplantation is evidence of this.

Other causes of acute renal impairment must always be excluded, such as volume depletion due to diuretics, sepsis and renal insufficiency due to the use of nephrotoxic drugs. An important precipitating factor is spontaneous bacterial peritonitis.

Progressive increase over several weeks is also seen in patients with difficult to treat ascites due to decreased cardiac output (due to heart failure) that can no longer fully compensate for the hypovolemia.

These phenomena can also superimpose on an underlying renal disease and this is called acute on chronic renal failure, which will not improve renal function after a liver transplant.

Treatment consists mainly of prevention. If an increase in creatinine is found, all diuretics should be stopped and albumin should be administered at a dose of 1g/kg body weight albumin 20% for two days. If the patient does not respond to this, terlipressin should be started intravenously (bolus injections 0.5 mg every 4 to 6 hours). Untreated, this complication has a mortality of 100%.

Presents as a patient with ascites and dyspnea. Hepatic hydrothorax occurs after a period of difficult to treat ascites. This is a massive pleural effusion, mainly on the right. The right diaphragm has openings. The decreased intrathoracic pressure sucks the ascitic fluid from the abdomen. The treatment is to drastically control the portal hypertension, using TIPS if the MELD score is not too high. Ultimately, hepatic hydrothorax is an indication for liver transplantation.

Presents as drowsiness in a patient with indirect signs of cirrhosis. During the course of their disease, 30% of patients develop hepatic encephalopathy. This concerns psychological and neurological disorders in patients with liver disease. Hepatic encephalopathy occurs in patients with both acute liver failure and cirrhosis.

Clinical examination may reveal the following abnormalities:

- Foetor hepaticus;

- Flapping tremor;

- Parkinsonian extrapyramidal symptoms.

There are four stages:

- Stage 1: reversal of the day-night rhythm, with daytime sleepiness and constitutional apraxia (impaired writing and impaired digit connection test);

- Stage 2: disorientation in time and space, flapping tremor, hyperreflection and rigidity;

- Stage 3: stupor, hyporeflexia and foot clonus;

- stage 4: coma.

Clinically, three stages are distinguished:

- minimal HE (can only be determined by psychometric testing);

- 'covert' HE (grade &) (can be determined by means of the 'animal naming test', in which the patient has to name as many animals as possible in one minute);

- 'overt' HE (grade 2 to 4).

In a cirrhotic patient, hepatic encephalopathy occurs due to a combination of insufficient synthesis activity of the liver and pronounced shunting. The reduced synthesis capacity causes an increase in serum ammonia. There is an increase in Blood-Brain-Barrier permeability (mainly only permeable to water). This leads to swelling of the astrocytes and a mild form of cerebral edema.

Large portosystemic shunts (larger than 8 mm in diameter) can occur anywhere. The two most common are splenorenal shunts (between the vena lienalis and the vena renalis) and at the opening of the umbilical veins.

Hepatic encephalopathy can be provoked by an increase in ammonia supply due to gastrointestinal bleeding or constipation, by hypo- and hypernatremia (diarrhea due to lactulose), by acidosis (spironolactone overdose), by the use of conventional sleeping medication and sedatives, by infections and by TIPS. Over time, the additional breakdown of ammonia via the muscles and kidneys also fails.

There is no gold standard for making a diagnosis. Diagnosis is based on the clinic. A rise in serum venous ammonia may be helpful, but is not valuable in patients with known cirrhosis.

In patients with alcoholic cirrhosis who are found in a coma, a differential diagnosis with a subdural hematoma should always be made.

In patients without liver disease but with increased venous ammonia encephalopathy, the presence of a congenital urea cycle deficiency or congenital extrahepatic portosystemic shunts (Abernethy malformation) must be excluded.

Treatment consists mainly of finding and correcting the provoking factors. There is no place for low-protein diets. The first line of treatment is lactulose with the aim of obtaining at least two soft stools per day. This can be given orally, or in the case of stupor or coma, with the aid of enemas (dilute 150 ml lactulose with 350 ml water). Under the influence of the bacterial flora, lactulose is broken down into acids. These give rise to the formation of ammonium, which cannot diffuse into the blood. This results in acid dialysis with a decrease in ammonia. Another explanation is the laxative effect.

The current second-line therapy consists of rifaximin 550mg twice daily. It is a non-absorbable antibiotic. The exact mechanism of action is unknown, but the intestinal barrier function improves and there is an increased activity of the enzymes involved in liver detoxification.

In case of large spontaneous porto-systemic shunt and a preserved liver synthesis capacity: embolization of the spontaneous porto-systemic shunt. In case of TIPS: reduction stent.

Presents as cyanosis in a patient with advanced liver disease. This is a functional right-left shunt due to dilation of the vascular bed, due to the increased concentrations of nitric oxide in the blood. Clinically, the central cyanosis and tachypnea are noticeable. The patient may develop clubbing of the fingers.

Severe hepatopulmonary syndrome occurs when the PaO2 < 70 mm Hg. The diagnosis is made with echocardiography with contrast. In this case, the bubbles appear immediately in the left half of the heart, after three beats. The only good treatment is liver transplantation.

In every patient with dyspnea, this must be ruled out. Screening can be done using echocardiography. This examination usually overestimates the pulmonary pressures. The diagnosis is made using cardiac catheterization, to examine the right side of the heart. Failure to recognize this can lead to sudden death during a surgical procedure. The cause of death in these patients is sudden death.

The differential diagnosis must be made with pulmonary hypertension due to left heart failure and other forms of pulmonary arterial hypertension, such as systemic diseases and drug-induced forms. The patients are eligible for pulmonary arterial hypertension-lowering medication.

Liver transplantation is indicated on the one hand when there is no other alternative. On the other hand, the chance of success must be sufficiently large, since there is a shortage of organs. Some countries have legislation that promotes organ donation: donation via the principle of presumed consent. Which in itself can also raise deeper ethical questions.

The donor liver is implanted in the place of the original liver (orthotopic). When implanting the donor liver, connections are made to the hepatic artery, the vena cava and the portal vein. A part of the donor and recipient bile ducts are attached to each other (duct-to-duct anastomosis).

The main indications for liver transplantation are HCC and/or end-stage cirrhosis. The patient with the worst short-term prognosis has priority. For end-stage cirrhosis, the urgency is determined using the MELD score. Patients with HCC can be granted a standard exception. This means that they spontaneously receive extra MELD points every month, so that they can still be transplanted despite a low MELD score. A very poor quality of life can also be an indication, such as in patients with PCLD and malnutrition, PBC patients with severe pruritus and PSC patients with regular hospital admissions due to cholangitis.Contraindications for liver transplantation are patients with a greatly increased surgical risk due to comorbidities and insufficient compliance, such as patients with alcoholic cirrhosis who have a higher risk of relapse of alcohol abuse after transplantation. If HCC is the indication, the lesions must fall within the Milan criteria. is means that the number of lesions must be limited, that they may not be too large and that there may be no extrahepatic locations (such as macrovascular invasion in the portal vein). In these situations, there is a high probability of micrometastases that will grow rapidly due to immunosuppression. When selecting patients, it is taken into account that a one-year survival of more than 90% and a five-year survival of 80% are sought.

In the donor selection, the body type (height and weight) and the blood group of the donor and the acceptor are taken into account. In adults, cadaver livers (deceased persons) are almost exclusively used. In the case of small children, relatives can donate part of their liver (living donation). Usually the donation comes from a person who is brain dead due to an underlying disease, such as a cerebral hemorrhage, trauma, ... Until recently, a necessary spontaneous circulation of the blood (heart beating) was assumed. Since recently, non-heart beating donors are increasingly used. These are deceased patients, where the circulation stops spontaneously when the ventilation is stopped in intensive care.

All sorts of complications can occur after a liver transplant. Poor liver quality (post-factum) can cause primary non-function, especially in steatotic livers. The following technical problems can occur:

- post-bleeding;

- thrombosis of the hepatic artery;

- a bile leak at the choledochal anastomosis.

During the first few weeks, the patient must take a high dose of immunosuppressants and is at increased risk of bacterial infections or CMV (cytomegalovirus) infection. Patients are therefore given prophylaxis with antibiotics and, if necessary, ganciclovir during this period. T-cell mediated rejection (acute rejection) occurs in approximately 20% of patients, but can usually be successfully treated by increasing immunosuppression. Only rejections occurring more than 90 days after liver transplantation affect the prognosis. In contrast to other organ transplants, chronic (ductopenic) rejection after liver transplantation is very rare.

The most common complications after liver transplantation are biliary complications. Most often, these are ischemic strictures of the intrahepatic bile ducts. This ischemia occurs during the removal of the liver. The strictures must be treated endoscopically with balloon dilatations and by placing stents. They can sometimes be a reason for retransplantation. Strictures at the biliary anastomosis, between the donor and recipient choledochus, can be treated more easily endoscopically.

The basic immunosuppression after liver transplantation are calcineurin inhibitors, such as tacrolimus. Mycophenolate mofetil or everolimus are added to these. Calcineurin inhibitors have the disadvantage that they reduce kidney function, so the blood level must be kept as low as possible. Patients after liver transplantation are at increased risk for certain malignancies, including non-melanoma skin tumors, post-transplant lymphomas, and colorectal tumors in patients transplanted for PSC. Patients who smoke and have a history of alcohol use are also at increased risk for lung tumors.

Several diseases, such as PSC and PBC, can recur late after a liver transplant. However, the main cause of death after years is cardiovascular disease, due to metabolic syndrome.

It should be taken into account that the lab tests can be disturbed by pregnancy. For example, there is a two- to fourfold increase in alkaline phosphatases due to placental production. There are three liver diseases that occur exclusively during pregnancy.

Presents in pregnant patients with pruritus and increased bile salts. This is the most frequent pregnancy-related liver disease. Pathogenesis is based on a dysfunction of bile transporters in patients with a genetic predisposition. From the 26th week onwards, the patient develops pruritus without a rash and there is a significant increase in serum bile salts.

The prognosis is usually benign for the mother. It gives rise to 20% mortality in the child. There is a risk if the bile salts are >40 micromol/l. The disease disappears immediately after induction of labor. Recurrence may occur in a subsequent pregnancy. Treatment consists of ursodeoxycholic acid (15mg/kg/day) and induction of pregnancy.

Presents in pregnant patients with pruritus and increased bile salts. This is the most frequent pregnancy-related liver disease. Pathogenesis is based on a dysfunction of bile transporters in patients with a genetic predisposition. From the 26th week onwards, the patient develops pruritus without a rash and there is a significant increase in serum bile salts. The prognosis is usually benign for the mother. It leads to 20% mortality in the child. There is a risk if the bile salts are > 40 micromol/l. The disease disappears immediately after induction of labor. Recurrence may occur in a subsequent pregnancy. Treatment consists of ursodeoxycholic acid (15 mg/kg/day) and induction of pregnancy.

Presents with abnormal liver tests and right hypochondrium pain in the pregnant patient. HELLP syndrome occurs in 1 in 1000 pregnancies in the second and third trimester. This is a systemic endothelial dysfunction. HELLP syndrome is part of preeclampsia. This is characterized by proteinuria, edema and increased blood pressure. Biochemically, hemolysis is found (H), increased transaminases above 100 IU/l (EL: Elevated Liver Tests) and decreasing platelets < 100000. Endothelial dysfunction can lead to liver hematomas due to rupture. This gives a mortality of 1 to 3% in the mother and 30% in the child. Treatment consists of addressing preeclampsia and early induction of labor.

Presents as acute liver failure during pregnancy. It occurs in 1 in 7,000 to 1 in 13,000 pregnant women in the third trimester. The pathogenesis is not well understood, but is probably due to accumulation of free fatty acids. Biochemically there are signs of acute liver failure, such as an increase in the INR. However, there is no strong increase in ALT. It has a high mortality for mother and child. Treatment is induction and if necessary liver transplantation.

Sepsis: causes severe functional reversible cholestasis.

'Bystander' hepatitis: extrahepatic infections can cause an asymptotic increase in transaminases.

Parenteral nutrition: excessive carbohydrate consumption causes steatosis and excessive lipid consumption causes cholestasis. It is also a triggering factor for gallbladder stones.

Hyperthyroidism: liver dysfunction can be caused directly by thyroid dysfunction or as a result of the use of antithyroid drugs (including Strumazol and Propylthiouracil).

Presents as pain in the right hypochondrium with hectic fever.

A liver abscess is an accumulation of pus in a necrotic cavity of the liver. A pyogenic liver abscess is caused by bacteria that can reach the liver in different ways:

- from the portal area: appendicitis, diverticulitis;

- from the gallbladder or bile ducts: as in empyema of the gallbladder and cholangitis;

- from the arterial area: as in sepsis.

The causative germs are usually Escherichia coli or other classical intestinal bacteria. The diagnosis can be difficult because the symptoms are sometimes not very pronounced. Typical symptoms are: pain in the right hypochondrium; hectic fever with leukocytosis and toxic condition of the patient. Clinical examination reveals liver palpitations. Diagnosis is made by ultrasound or CT scan with intravenous contrast, hemocultures, or ultrasound or CT-guided puncture with culture. Treatment consists of broad-spectrum antibiotics. If the patient remains highly toxic, percutaneous ultrasound or CT-guided puncture and drainage is indicated. Surgical drainage of a liver abscess is rarely necessary.

An amoebic liver abscess is caused by the anaerobic parasite Entamoeba histolytica. It occurs in the tropics and causes amoebic dysentery (bloody stools) as a result of contaminated water or food. The pathogenic parasite reaches the bloodstream from the intestine, so that in addition to a liver abscess, lung or brain abscesses can also occur. The liver abscess is usually solitary and located in the right lobe of the liver. The clinic of an amoebic liver abscess is similar to that of a pyogenic liver abscess. The diagnosis is made by serology and stool examination. Treatment consists of metronidol. Percutaneous drainage is rarely necessary.

The disease is caused by a parasite with the shape of a small tapeworm: usually Echinococcus granulosus. It is a parasite of dogs and foxes. Humans can be infected by ingesting contaminated food, such as blueberries, blackberries and insufficiently washed vegetables. The incubation period can last years. The parasite migrates from the intestine via the portal vein to the liver. There it forms a hydatid cyst, the inner wall of which is covered with multiple embryonic tapeworm heads. The outer wall of the cyst can calcify. The echinococcus cyst usually occurs solitary in the right lobe of the liver. Multiple cysts are possible in 30% of cases.

The liver cyst can cause pain in the right hypochondrium and can lead to hepatomegaly. Rupture of the cysts to the bile ducts can occur in 20% of cases, resulting in painful jaundice. Echinococcus multilobularis is a more aggressive parasite that also has localizations in the lungs. It can give an image of a primary liver neoplasm in the liver. The diagnosis is made on the basis of CT or MRI scan. Biochemically there is eosinophilia and the diagnosis can be made on the basis of serology. Treatment consists of surgical resection with pre- and postoperative administration of mebendazole or albendazole. In that case, a cystectomy is performed, in which the germinative layer of the echinococcal cyst is resected after intraoperative sterilization of the contents with hypertonic sodium chloride, to prevent dissemination.

Presents as frequent incidental finding in the liver.

Solitary liver cysts are very common and are usually found incidentally on imaging. A distinction must be made with PCLD, in which by definition more than twenty cysts are present. Solitary biliary cysts do not cause symptoms. Consequently, atypical upper abdominal complaints cannot be attributed to an incidentally found liver cyst. Large cysts can sometimes compress the surrounding organs due to their volume. This results in a rapid feeling of satiety. Very rarely, such a cyst can become infected.

The diagnosis is made by ultrasound, or a CT or MRI scan. A distinction must be made between a cystadenoma and cystadenocarcinoma (very rare). Percutaneous or CT-guided puncture aspiration usually gives very rapid recurrence, unless alcoholization occurs. Very rarely surgery is necessary, in which a marsupialation or fenestration is performed.

Presents as an incidental finding in the liver.

This involves a tangle of blood vessels with fibrous tissue, probably congenital. It occurs in 4% of the population. It is a benign tumor that does not cause any symptoms and does not need to be treated. The diagnosis is made by the typical characteristics on CT or MRI scan. Very rarely there may be platelet consumption or it may concern enlarged lesions (giant hemangioma).

Presents in women using oral contraception.

The liver cell adenoma occurs mainly in young women using oral contraception. Very rarely it is provoked by the intake of anabolic steroids in men. The diagnosis is made by the typical characteristics on CT or MRI scan. The lesion does not contain bile ducts and porat fields. Recently, different histological types have been distinguished. Lesions containing beta-catenin mutation are precancerous.

Liver adenoma can be complicated by bleeding. Rarely, it can degenerate if it is larger than five centimeters. When the diagnosis is made, oral contraception must be stopped. Then one can wait six to twelve months. If the lesion is still larger than five centimeters after this period, it must be resected. In men, the chance of complications is very high and surgery must always be performed.

Very rarely, more than ten adenomas can occur (polyadenomatosis). This is sometimes accompanied by liver steatosis in young women. The approach is similar to the solitary adenoma. In case of overweight, the patient is advised to lose weight.

Presents as an incidental finding in the liver.

This is a local hyperplasia in response to a defect in a large arterial blood vessel. The lesion is usually solitary. The diagnosis is made by the typical characteristics on a CT or MRI scan, for example the central star-shaped structure. FNH does not cause any complaints and is not complicated. Consequently, there is no indication for resection.