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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.

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