Pathologies

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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.

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