Portal hypertension overview

# Overview
Based on the etiology, portal hypertension may be classified as pre-hepatic, intra-hepatic, and post-hepatic. Intra-hepatic portal hypertension classified into pre-sinusoidal, sinusoidal, and post-sinusoidal disorders. Based on the function impairment in the liver, portal hypertension may be classified as cirrhotic and non-cirrhotic. The exact pathogenesis in portal hypertension is disturbance in normal physiology of portocaval circulation. The main factors that affect the pressure gradient in blood vessels are blood flow (Q) and vessel radius (r) in a direct and inverse way, respectively. Portal hypertension is related to elevation of portal vasculature resistance. Peripheral vasodilatation is the basis for decreased systemic vascular resistance and mean arterial pressure, plasma volume expansion, elevated splanchnic blood flow, and elevated cardiac index. Fourteen different genes are involved in the pathogenesis of portal hypertension. Homozygous missense mutation in DGUOK gene is found to be related with non-cirrhotic portal hypertension. On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension. The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome. Pharmacological medical therapy is recommended among patients with cirrhosis and portal hypertension which are without esophageal varices, with esophageal varices but not yet bleeding, with esophageal varices that is bleeding, and with esophageal varices that has already bled. Pharmacological medical therapies for portal hypertension include non-selective beta blockers (NSBB), analogues of nitric oxide (NO), and vasoactive agents. Surgery is not the first-line treatment option for patients with portal hypertension. Surgery is usually reserved for patients with either severe cirrhosis, esophageal varices, splenomegaly, ascites, or liver failure. There are no established measures for the primary prevention of portal hypertension. Effective measures for the primary prevention of liver diseases, as the main causes of portal hypertension, include hepatitis B vaccination, avoiding unprotected sex relations, precise screening of the blood products before infusion, alcohol consumption reduction, overweight and obesity prevention, and diabetes mellitus prevention. There are also no established measures for the secondary prevention of portal hypertension. Effective measures for the secondary prevention of liver diseases, as the main causes of portal hypertension, include treatment of hepatitis B and hepatitis C infections, alcohol abuse management, weight loss or management, and proper management of diabetes mellitus.

# Historical Perspective
In 1511, Leonardo da Vinci, Italian Renaissance polymath, first describe the portal hypertension in an illustration in his textbook "De humanis corpore". ... the artery and the vein which go from the spleen to the liver become so large, to block the blood coming from the mesenteric vein; the latter vein dilates and becomes tortuous like a snake, that the liver dries and become like frozen bran, in colour and consistency..., this presentation was inaccurately described as the cause of portal hypertension. In 1937, William Thompson, a Canadian biologist, measured the portal vein pressure for the first time. He did the measurements in the open abdomen for both inferior vena cava (IVS) and portal vein. In 1939, Crafoord and Fenckner, Dutch cardiac surgeons, used sclerosing agents (quinine solutions) to treat the esophageal varices via endoscopy. The procedure was rarely used because of high rates of re-bleeding. In 1980s, researchers have observed that endoscopic sclerotherapy is more efficient than surgical shunting in preventing recurrent variceal bleeding. In 1967, Thomas Earl Starzl, an American physician, mentioned that liver transplantation is the only way to treat both portal hypertension and the underlying hepatic disease.

# Classification
Based on the etiology, portal hypertension may be classified as pre-hepatic, intra-hepatic, and post-hepatic. Intra-hepatic portal hypertension classified into pre-sinusoidal, sinusoidal, and post-sinusoidal disorders. Based on the function impairment in the liver, portal hypertension may be classified as cirrhotic and non-cirrhotic.

# Pathophysiology
The exact pathogenesis in portal hypertension is disturbance in normal physiology of portocaval circulation. The main factors that affect the pressure gradient in blood vessels are blood flow (Q) and vessel radius (r) in a direct and inverse way, respectively. Portal hypertension is related to elevation of portal vasculature resistance. Peripheral vasodilatation is the basis for decreased systemic vascular resistance and mean arterial pressure, plasma volume expansion, elevated splanchnic blood flow, and elevated cardiac index. Fourteen different genes are involved in the pathogenesis of portal hypertension. Homozygous missense mutation in DGUOK gene is found to be related with non-cirrhotic portal hypertension. On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension. The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome.

# Causes
Life-threatening causes of portal hypertension include cirrhosis, severe portal venous obstruction or thrombosis (Budd-Chiari syndrome), and fulminant hepatic failure (e.g., due to hepatitis). Common causes for portal hypertension include alcoholic hepatitis, autoimmune disease, bacterial intestinal infections (e.g., recurrent E.coli infection), chronic hepatitis, cirrhosis, fatty liver, schistosomiasis, and sickle cell disease.

# Differentiating Portal Hypertension from Other Diseases
Portal hypertension must be differentiated from other diseases that cause ascites, splenomegaly, hematemesis or melena, bacterial peritonitis, hydrothorax, hypoxemia, and pulmonary hypertension. Diseases that must be differentiated from portal hypertension are malignant ascites, nephrogenic ascites, tuberculosis, thalassemia, sickle cell disease, hereditary spherocytosis, peptic ulcer disease, Mallory-Weiss tear, colorectal cancer, secondary bacterial peritonitis, malignant hydrothorax, sarcoidosis, nephrotic syndrome, heart failure, central nervous system depression, muscular weakness, idiopathic pulmonary hypertension, valvular heart disease, and connective tissue disease.

# Epidemiology and Demographics
The incidence of portal hypertension is approximately 25,000 cases per 100,000 individuals with non-alcoholic fatty liver disease (NAFLD). The prevalence of cirrhosis, as the main cause of portal hypertension, is approximately 270 cases per 100,000 individuals in the United States. The age-adjusted mortality rate of cirrhosis is approximately 18.1 deaths per 100,000 population, based on the report of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The incidence of portal hypertension increases in early 4th decade in females and early 3rd decade in males. Cirrhosis usually affects individuals of the non-Hispanic blacks and Mexican Americans more likely. For unknown reason, portal hypertension is more prevalent among people of low socioeconomic state.

# Risk Factors
There are no established risk factors for portal hypertension. Cirrhosis as the main cause of portal hypertension has various risk factors. Common risk factors in the development of cirrhosis include intravenous drug use (IVDU), tattooing or piercing in unhygienic condition, needlestick injury, blood transfusion before 1992, viral hepatitis, and unprotected sexual intercourse.

# Screening
There is insufficient evidence to recommend routine screening for portal hypertension.

# Natural History, Complications, and Prognosis
Portal hypertension is increased hepatic venous pressure gradient (HVPG) above 5 mmHg. The symptoms of portal hypertension usually develop in the third and fourth decades of life, and generally start with symptoms such as esophageal varices, caput medusae, spider angioma, and splenomegaly. Esophageal varices are typically developed 5-15% per year after cirrhosis. Most of the cirrhotic patients will develop the varices during the lifetime. Approximately 60% of patients with cirrhosis develop ascites in 10 years. 10% of hospitalized patients with cirrhosis will involve in spontaneous bacterial peritonitis (SBP). If left untreated, 20-40% of patients with SBP may progress to death. The presence of variceal bleeding, spontaneous bacterial peritonitis, and hepatorenal syndrome are associated with a particularly poor prognosis among patients with portal hypertension. They are the leading causes of death among patients with portal hypertension.

# Diagnosis

## Diagnostic Study of Choice
Diagnostic study of choice for diagnosing portal hypertension is to measure Hepatic venous pressure gradient (HVPG). HVPG measurement is the difference between hepatic venous wedge pressure (HVWP) and free hepatic venous pressure (FHVP). HVPG reflects the intra-sinusoidal pressure. HVPG is measured through insertion of a catheter in right internal jugular vein.

## History and Symptoms
The majority of patients with portal hypertension are asymptomatic. Patients with portal hypertension may have a positive history of intravenous drug use (IVDU), tattooing or piercing in unhygienic condition, needlestick injury, blood transfusion before 1992, viral hepatitis, and unprotected sexual intercourse. All of the clinical symptoms are associated with complications of the portal hypertension. Common symptoms of portal hypertension include hematemesis, melena, abdominal distention (ascites), fatigue, and loss of appetite.

## Physical Examination
Physical examination of patients with portal hypertension is usually remarkable for splenomegaly, caput medusae, and thrombocytopenia. The presence of jaundice on physical examination is highly suggestive of cirrhosis. Patients with portal hypertension usually appear ill and icteric.

## Laboratory Findings
There are no diagnostic laboratory findings exclusively associated with portal hypertension. Laboratory findings related with the diagnosis of cirrhosis, as the most common underlying disease for portal hypertension, include indirect serum markers and direct fibrosis markers. Indirect serum markers are platelet count, AST/ALT index, AST/platelet ratio index, and Lok score. Direct fibrosis markers are fibrotest, fibrometer, hepascore, hyaluronic acid, and enhanced liver fibrosis.

## Electerocardigram
There are no ECG findings associated with portal hypertension.

## X Ray
There are no x-ray findings associated with portal hypertension.

## CT scan
Abdominal CT scan may be helpful in the diagnosis of portal hypertension. Findings on CT scan suggestive of portal hypertension include re-canalized umbilical vein, dilated portal vein and/or splanchnic veins, esophageal varices, collaterals in any abdominal organ, splenomegaly, and ascites.

## MRI
Abdominal MRI may be helpful in the diagnosis of portal hypertension. Findings on MRI suggestive of portal hypertension include re-canalized umbilical vein, dilated portal vein and/or splanchnic veins, esophageal varices, collaterals in any abdominal organ, splenomegaly, and ascites.

## Echocardiography/Ultrasound
Echo-Doppler may be helpful in the diagnosis of portal hypertension. Findings on an echo-doppler suggestive of portal hypertension include lack of increase in portal vein diameter in response to meals, increased portal blood flow velocity, and decreased portal vein cross-sectional area. Color-Doppler ultrasound may be helpful in the diagnosis of portal hypertension. Findings on an color-doppler ultrasound suggestive of portal hypertension include increased diameter of left gastric vein, increased diameter of portal vein, and increased flow velocity in left gastric vein.

## Other Imaging Findings
Upper endoscopy may be helpful in the diagnosis of gasteroesophageal varices. Findings on an upper endoscopy diagnostic of esophageal varices include visible submucosal tortuous veins, congested veins without compression during air insufflation, and grape-like varicose veins that may occlude the lumen. Three dimensional portal venography may be helpful in the diagnosis of gasteroesophageal varices. Findings on a portal venography diagnostic of esophageal varices include reverse flow in porto-systemic shunts, collateral veins draining into inferior vena cava (IVC), and other collateral veins.

## Other Diagnostic Studies
Hepatic venous pressure gradient (HVPG) measurement  is the difference between hepatic venous wedge pressure (HVWP) and free hepatic venous pressure (FHVP). HVPG reflects the intra-sinusoidal pressure. HVPG is measured through insertion of a catheter in right internal jugular vein.

# Treatment

## Medical Therapy
Pharmacological medical therapy is recommended among patients with cirrhosis and portal hypertension which are without esophageal varices, with esophageal varices but not yet bleeding, with esophageal varices which is bleeding, and with esophageal varices which has already bled. Pharmacological medical therapies for portal hypertension include non-selective beta blockers (NSBB), analogues of nitric oxide (NO), and vasoactive agents.

## Surgery
Surgery is not the first-line treatment option for patients with portal hypertension. Surgery is usually reserved for patients with either severe cirrhosis, esophageal varices, splenomegaly, ascites, or liver failure.

## Primary Prevention
There are no established measures for the primary prevention of portal hypertension. Effective measures for the primary prevention of liver diseases, as the main causes of portal hypertension, include  hepatitis B vaccination, avoid unprotected sexual intercourse, precise screening of the blood products before infusion, reducing alcohol consumption, overweight and obesity prevention, and diabetes mellitus prevention.

## Secondary Prevention
There are no established measures for the secondary prevention of portal hypertension. Effective measures for the secondary prevention of liver diseases, as the main causes of portal hypertension, include treatment of hepatitis B and hepatitis C infections, alcohol abuse management, weight loss or management, and proper management of diabetes mellitus.